Phage Therapy Saves Toddler’s Life: Index #69

Phage Therapy Saves Toddler’s Life: Index #69

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.

A timeline of events. Several early-onset post-operative complications, including liver rejection…followed by an Escherichia coli and Enterococcus faecium sepsis, and cytomegalovirus (CMV) infection. At day 53 post-liver transplant, he entered a severe septicemia due to XDR Pseudomonas aeruginosa. BFC1 “bacteriofaagcocktail 1”, CMV cytomegalovirus, DDLT deceased-donor liver transplantation, EC ethics committee, LDLT living-donor liver transplantation, XDR extensively drug-resistant. From Van Nieuwenhuyse B. et al. in Nature Communications.

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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(↑ = recommended article, * = open access, † = review, comment, etc. )

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  • 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.

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↑*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.

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*The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems. Lasker K…Shapiro L. Nature Communications. Link

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*Analysis of the Human Protein Atlas Weakly Supervised Single-Cell Classification competition. Le T…Lundberg E. Nature Methods. Link

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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

↑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.

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*Activation of stably silenced genes by recruitment of a synthetic de-methylating module. Chan WF…Allan RS. Nature Communications. Link

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Chemically inducible split protein regulators for mammalian cells. Rihtar E…Jerala R. Nature Chemical Biology. Link

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*AssemblyTron: Flexible automation of DNA assembly with Opentrons OT-2 lab robots. Bryant Jr. JA…Wright RC. bioRxiv (preprint). Link

↑*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%.

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*Metabolic engineering of p-hydroxybenzoate in poplar lignin. Mottiar Y…Mansfield SD. Plant Biotechnology Journal. Link

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*†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

*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

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