Phage Therapy Saves Toddler's Life: Index #69
The child is alive and well two years later after a liver rejection and septicemia.
This year marks the 100-year anniversary of phage therapies. How fitting, then, that a paper out this week tells the story of a toddler — a boy from Algeria — who suffered from a life-threatening, drug-resistant infection after receiving a liver transplant.
In the days and weeks that followed the transplant, his body rejected the liver. E. coli and other bacteria entered his bloodstream. Severe septicemia, a life-threatening condition that ends in death for about half of those unlucky enough to experience it, swiftly set in. Antibiotics didn’t help, and he was running out of time.
On the 57th day after the liver transplant, his doctors settled on urgent action. Pointing to article 37 of the Declaration of Helsinki — which permits “an unproven intervention” to be used in the face of an unmet medical need — they filed for permission to use phage therapy on the toddler. This is an experimental, clinical procedure in which bacteriophages, or viruses that infect bacteria, are injected into the bloodstream to treat an infection. The ethics committee at the universities of Saint-Luc and UC Louvain, in Belgium, approved.
A call was placed to the Queen Astrid Military Hospital, in Brussels. There, Jean-Paul Pirnay and his team prepared a bacteriophage cocktail. It held a mixture of phages — one targeting Staphylococcus aureus and two targeting Pseudomonas aeruginosa — tailor-made to detect, infect, and destroy the harmful bacteria inside the child’s body.
All of the phages were sequenced and studied in detail. They were deemed safe.
And so this vial, holding this magical liquid, was taken to the toddler. A tiny amount, ten milliliters, was added to his IV drip bag. Every six hours, like clockwork, another ten milliliters were added. This routine persisted for the next seven days, to no avail.
Bacteria remained in the child’s bloodstream. So the next day, the bacteriophage dosage was doubled, to twenty milliliters every six hours. This continued for days, then weeks, then months — 77 more days in total.
At the end of it all, the bacteria were gone, vanished, missing. The toddler left the intensive care unit and went home with persistent fever and inflammation. Then, 72 days after the phage therapy had begun, another (noninfected) liver became available.
The organ was taken from a deceased donor. The boy’s faulty liver was removed for a second time. His abdominal cavity was rinsed with the bacteriophages. In went the new liver. The toddler went back onto IV drips with the phage cocktail and a veritable arsenal of antibiotics — cotrimoxazole, vancomycin, colistin, ganciclovir, fluconazole, aztreonam, and gentamycin — mixed in.
Now, more than two years later, the child is at home. He takes immunosuppressive medications but has had no further outbreaks. His liver remains healthy. He remains healthy.
This report is yet another reminder of the clinical power that phages wield. They’ve been underutilized since the 1950s, when the rise of antibiotics — coupled with the Soviet use of phage therapies — led to their gradual abandonment.
But it was before all that, in 1922, that Parisian microbiologist Felix d’Hérelle first showed that phages could eradicate “dysentery and other bacilli” in rabbits and small animals. It was an amazing result then, and it’s a lifesaving result now.
Yes, phage therapy works best in immunocompromised people because they can’t mount an effective immune response. Yes, it’s still difficult to design phages that work as expected. But with the rise of antibiotic resistance, and the waning power and profit margins in developing new antibiotics, it’s time we build a future around phages and the past.
Thanks for reading,
— Niko McCarty
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Synthetic Biology Index
(↑ = recommended article, * = open access, † = review, comment, etc. )
↑*Visualizing translation dynamics at atomic detail inside a bacterial cell. Xue L…Mahamid J. Nature. Link
A must-read this week. If time is short, at least check out the Supplemental Videos. The ribosome was captured in 13 different conformations using cryo-electron tomography, thus creating atomic-detail videos of the ribosome in action.
*Transcription factors interact with RNA to regulate genes. Oksuz O…Young RA. bioRxiv (preprint). Link
*Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform. Siepe DH…Garcia KC. eLife. Link
*Nature of epigenetic aging from a single-cell perspective. Tarkhov AE…Gladyshev VN. bioRxiv (preprint). Link
*Expansion of the global RNA virome reveals diverse clades of bacteriophages. Neri U…Gophna U. Cell. Link
Characterization of the self-targeting Type IV CRISPR interference system in Pseudomonas oleovorans. Guo X…Randau L. Nature Microbiology. Link
Biomanufacturing & Metabolic Engineering
↑*Genome-scale mapping of functional genes and loci in bacteria for industrial phenotypes. Yuan Y…Zhang C. bioRxiv (preprint). Link
Base editors were used to deactivate 89% of the genes in E. coli bacteria, and to mutate 31,566 additional sites in the genome. The result is a detailed map of those genes that contribute to growth in E. coli — 170 candidates in total.
↑*Synthetic carbon fixation via the autocatalytic serine threonine cycle. Wenk S…Bar-Even A. bioRxiv (preprint). Link
*Engineering nucleotide sugar synthesis pathways for independent and simultaneous modulation of N-glycan galactosylation and fucosylation in CHO cells. Prabhu A, Shanmugam D & Gadgil M. Metabolic Engineering. Link
*†Biosynthesis of alkanes/alkenes from fatty acids or derivatives (triacylglycerols or fatty aldehydes). Monteiro RRC…Fernandez-Lafuente R. Biotechnology Advances. Link
*Glycosyltransferases engineering and multi-glycosylation routes development facilitating biosynthesis of high-intensity sweetener mogrosides. Li J…Sun Y. iScience. Link
↑*Top-down design of protein nanomaterials with reinforcement learning. Lutz ID…Baker D. bioRxiv (preprint). Link
†Multienzymatic synthesis of nylon monomers from vegetable oils. Lin L…Huang H. Trends in Biotechnology. Link
Build A Cell
*†A four-track perspective for bottom-up synthetic cells. Stano P. Frontiers in Bioengineering and Biotechnology. Link
*Actomyosin-Driven Division of a Synthetic Cell. Baldauf L…Koenderink GH. ACS Synthetic Biology. Link
*Phospholipid synthesis inside phospholipid membrane vesicles. Eto S…Kuruma Y. Communications Biology. Link
Self-assembly of emulsion droplets through programmable folding. McMullen A…Brujic J. Nature. Link
*The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems. Lasker K…Shapiro L. Nature Communications. Link
Computational Tools & Models
*Deciphering microbial gene function using natural language processing. Miller D, Stern A & Burstein D. Nature Communications. Link
*Analysis of the Human Protein Atlas Weakly Supervised Single-Cell Classification competition. Le T…Lundberg E. Nature Methods. Link
*Ribocentre: a database of ribozymes. Deng J…Huang L. Nucleic Acids Research. Link
*GotEnzymes: an extensive database of enzyme parameter predictions. Li F…Nielsen J. Nucleic Acids Research. Link
*AlloMAPS 2: allosteric fingerprints of the AlphaFold and Pfam-trRosetta predicted structures for engineering and design. Tan ZW…Berezovsky IN. Nucleic Acids Research. Link
Biofoundry Palette: Planning-Assistant Software for Liquid Handler-Based Experimentation and Operation in the Biofoundry Workflow. Ko SC…Woo HM. ACS Synthetic Biology. Link
*Assessing single-component gene drive systems in the mosquito Aedes aegypti via single generation crosses and modeling. Reid W…Franz AWE. bioRxiv (preprint). Link
GroovDB: A Database of Ligand-Inducible Transcription Factors. d’Oelsnitz S…Ellington AD. ACS Synthetic Biology. Link
*Data-based dynamic compartment model: Modeling of E. coli fed-batch fermentation in a 600 m3 bubble column. Bisgaard J…Gernaey KV. Journal of Industrial Microbiology and Biotechnology. Link
CRISPR, Gene Editing & Control
↑Engineered CRISPR prime editors with compact, untethered reverse transcriptases. Grünewald J…Joung JK. Nature Biotechnology. Link
Prime editors are proteins — typically Cas9 fused to a reverse transcriptase — that can make programmable substitutions, insertions, or deletions in the genome. Turns out, these two proteins don’t need to be fused together at all. A lone Cas9 and lone reverse transcriptase “function as efficiently as intact PE2 [prime editor] in human cells.” This discovery was used to make more compact prime editors that can more easily fit into AAVs for gene therapy.
↑*A competitive precision CRISPR method to identify the fitness effects of transcription factor binding sites. Pihlajamaa P…Taipale J. Nature Biotechnology. Link
*Activation of stably silenced genes by recruitment of a synthetic de-methylating module. Chan WF…Allan RS. Nature Communications. Link
*Quantification of Genome Editing and Transcriptional Control Capabilities Reveals Hierarchies among Diverse CRISPR/Cas Systems in Human Cells. Escobar M…Hilton IB. ACS Synthetic Biology. Link
Chemically inducible split protein regulators for mammalian cells. Rihtar E…Jerala R. Nature Chemical Biology. Link
Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks. Marciano S…Herfert K. PNAS. Link
Efficient multitool/multiplex gene engineering with TALE-BE. Boyne A…Juillerat A. Frontiers in Bioengineering and Biotechnology. Link
*CRISPR/Cas9 mediated gene editing in non-model nematode Panagrolaimus sp. PS1159. Hellekes V…Kroiher M. bioRxiv (preprint). Link
*Genome editing using a versatile vector-based CRISPR/Cas9 system in Fusarium species. Shinkado S…Kamakura T. Scientific Reports. Link
DNA Synthesis & Assembly
*AssemblyTron: Flexible automation of DNA assembly with Opentrons OT-2 lab robots. Bryant Jr. JA…Wright RC. bioRxiv (preprint). Link
Medicine & Diagnostics
↑*In situ targeted mutagenesis of gut bacteria. Brodel AK…Bikard D. bioRxiv (preprint). Link
A remarkable paper that offers a new approach for directly engineering microbes in the gut. A bacteriophage was engineered to carry a gene encoding a base editor. These bacteriophages were then injected into the esophagus of mice. The base editor gene was housed on a non-replicating plasmid, which is destroyed by the gut unless an IPTG inducer is added to the animals’ food or water. When 4 billion phages were injected into a mouse, the base editing efficiency was about 32%.
↑*Bacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler. Van Nieuwenhuyse B…Pirnay J-P. Nature Communications. Link
↑*In vivo peptide-based delivery of a gene-modifying enzyme into cells of the central nervous system. Allen JK…Pellois J-P. Science Advances. Link
*Molecular diagnostics for early detection of invasion of malaria vector Anopheles stephensi. Singh OP…Mallick PK. bioRxiv (preprint). Link
GPRC5D-Targeted CAR T Cells for Myeloma. Mailankody S…Smith EL. The New England Journal of Medicine. Link
*Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Bittner S…Feuerer M. PNAS. Link
*In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis. Zhou X…Chen X. Nature Communications. Link
*Potent monoclonal antibodies neutralize Omicron sublineages and other SARS-CoV-2 variants. Chen Z…Farci P. Cell Reports. Link
*†Synthetic Biology Technologies And Genetically Engineering Strategies For Enhanced Cell Therapeutics. Li S…Sun C. Stem Cell Reviews and Reports. Link
*†CRISPR/Cas9 in the era of nanomedicine and synthetic biology. Schmidt TJN…Raffa V. Drug Discovery Today. Link
*Metabolic engineering of p-hydroxybenzoate in poplar lignin. Mottiar Y…Mansfield SD. Plant Biotechnology Journal. Link
Recombinase Polymerase Amplification Coupled with CRISPR-Cas12a Technology for Rapid and Highly Sensitive Detection of Heterodera avenae and Heterodera filipjevi. Shao H…Peng H. Plant Disease. Link
Tissue, Protein & Molecular Engineering
↑*Reprogramming Adeno-Associated Virus Tropism Via Displayed Peptides Tiling Receptor-Ligands. Portell A…Mali P. bioRxiv (preprint). Link
Reprogramming the Cleavage Specificity of Botulinum Neurotoxin Serotype B1. Cleveland JD…Tucker CL. ACS Synthetic Biology. Link
Enhanced small green fluorescent proteins as a multisensing platform for biosensor development. Liang G-T…Piatkevich K. Frontiers in Bioengineering and Biotechnology. Link
Engineered Protein Nanocages for Concurrent RNA and Protein Packaging In Vivo. Kwon S & Giessen TW. ACS Synthetic Biology. Link
Tools & Technology
↑*Opto-katanin, an optogenetic tool for localized, microtubule disassembly. Meiring JCM…Akhmanova A. Current Biology. Link
↑*RNA cytometry of single-cells using semi-permeable microcapsules. Leonaviciene G & Mazutis L. bioRxiv (preprint). Link
*Drug interaction mapping with proximity dependent enzyme recruiting chimeras. Venable JD…Brock A. bioRxiv (preprint). Link
*†Light-regulated Gene Expression in Bacteria: Fundamentals, Advances, and Perspectives. Ohlendorf R & Möglich A. Frontiers in Bioengineering and Biotechnology. Link
*Long-read single-molecule RNA structure sequencing using nanopore. Bizuayehu TT…Valen E. Nucleic Acids Research. Link
Time-resolved single-cell RNA-seq using metabolic RNA labelling. Erhard F…Dölken L. Nature Reviews Methods Primers. Link
*Cell type-independent profiling of interactions between intracellular pathogens and the human phosphoproteome. Mohler K…Rinehart J. bioRxiv (preprint). Link
*The VersaLive platform enables microfluidic mammalian cell culture for versatile applications. Nocera GM…diBernardo D. Communications Biology. Link
*Organellar Glue: A Molecular Tool to Artificially Control Chloroplast–Chloroplast Interactions. Ichikawa S…Kodama Y. ACS Synthetic Biology. Link
Other Interesting Stuff
*Climate change may outpace current wheat breeding yield improvements in North America. Zhang T…Yang X. Nature Communications. Link
*Gendered citation patterns among the scientific elite. Lerman K…Pujara J. PNAS. Link
*†The art and science of building castles in the sky and houses of cards that don’t collapse. Goldstein JL. Cell. Link