Microbial Community Capsules

In nature, microbes work together to ferment kombucha, beer and wine. They age our cheese, fix nitrogen in the soil, decompose organic waste and digest our food.

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The first science paper that I ever wrote was about microbial communities and how to engineer them. It was just a review, and definitely wasn’t published in Science (capital ‘S’), but it made me feel connected to a topic in a way that I never had before. I learned about the rich potential in microbes working together — distributed biocomputation, shared resources, specialization, reduction of metabolic burden — but then, reluctantly, left the field completely. A new study in Nature Communications has reignited my interest.

In nature, microbes work together to ferment kombucha, beer and wine. They age our cheese, fix nitrogen in the soil, decompose organic waste and digest our food. In the lab, our goals with such communities are usually application-specific, and people work on whatever problems seem most palatable to funding agencies, like coaxing microbes to produce biomethane or pharmaceuticals.

But microbes did not evolve over the last 3.7 billion years to follow the whims of some sweaty, underpaid scientist in a dimly-lit lab. And it’s really difficult to engineer a microbial community to do much of anything. One species usually grows very fast and swiftly takes over the other populations, much like the bunnies in my backyard. And, in nature, microbes organize into complex spatial patterns that enhance their stability. In the lab, we basically just mix shit up and hope for the best.

To make more stable and controllable communities of microbes, researchers from the Shenzhen Institute of Synthetic Biology didn’t appeal to nature — they reinvented the wheel.

Specifically, they encapsulated cells in microcapsules, built from cross-linked polymers, that allow for proteins and small molecules to be freely exchanged. I’d imagine that all these microcapsules, mixed together, look a bit like Orbeez in a flask. And, honestly, I’m not far off (just see Figure 4 in the paper).

In one experiment, different strains of E. coli were each engineered to produce one protein needed to create the PURE cell-free system (there are 34 proteins required, in total). The population of each strain — and the amount of a given protein — could be tuned just by adding more or less of these ‘Orbeez’.

In later tests, the researchers built an E. coli-yeast co-culture, a three-way community with E. coli, S. cerevisiae and C. glutamicum, and a phototropic co-culture with S. elongatus and E. coli. Every experiment seems remarkably simple; almost trivial. Just makes some microcapsules, shove some cells inside, and mix them in a pot.

There are some obvious benefits to this whole Orbeez approach:

  1. Cells are physically limited to their capsule and so cannot divide ad infinitum or overwhelm the other cells.
  2. The community’s composition is easily defined. Want to divide a population 50-50? Just count out the capsules and add equal parts to the pot.
  3. Biocontainment is a breeze (unless, you know, the microcapsules degrade.)
  4. Extracting a biomanufactured drug or biofuel is a breeze. Just centrifuge the flask of microcapsules and pull off the supernatant.

A bigger question, though, is whether this approach will be feasible at scale. If the ultimate goal of engineering microbial communities is to do something useful for the world, then everything should probably be built with bioreactors, and scale, and feasibility in mind. How hard is it to make these microcapsules? (Seriously, I don’t know). How can we dynamically control cell populations if it’s only possible to add in more microcapsules (perhaps we could use antibiotics to kill certain strains, but then their cocoons just sit there forever)?

In looking for solutions to challenging problems, I’d still bet on Mother Nature.

Read more at Nature Communications.

Other Papers

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

Assembly, Synthesis & Sequencing

↑*Oxford Nanopore R10.4 long-read sequencing enables the generation of near-finished bacterial genomes from pure cultures and metagenomes without short-read or reference polishing. Sereika M…Albertsen M. Nature Methods. Link

FRAGLER: A Fragment Recycler Application Enabling Rapid and Scalable Modular DNA Assembly. Öling D…Roth R. ACS Synthetic Biology. Link

Basic Research

*Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis. Sun M & Zhang J. Science Advances. Link

*Large excess capacity of glycolytic enzymes in Saccharomyces cerevisiae under glucose-limited conditions. Grigaitis P & Teusink B. bioRxiv (preprint). Link

↑*Slow molecular evolution of rubisco limits adaptive improvement of CO2 assimilation. Bouvier JW, Emms DM & Kelly S. bioRxiv (preprint). Link

*Biochemical noise enables a single optogenetic input to control identical cells to track asymmetric and asynchronous reference signals. May MP & Munsky B. bioRxiv (preprint). Link

Biomanufacturing & Metabolic Engineering

↑*Biosynthesis of strychnine. Hong B…O’Connor SE. Nature. Link

↑*Using fungible biosensors to evolve improved alkaloid biosyntheses. d’Oelsnitz S…Ellington AD. Nature Chemical Biology. Link

*Activating natural product synthesis using CRISPR interference and activation systems in Streptomyces. Ameruoso A…Chappell J. Nucleic Acids Research. Link

Efficient Production of a Functional Human Milk Oligosaccharide 3′-Sialyllactose in Genetically Engineered Escherichia coli. Zhang J…Mu W. ACS Synthetic Biology. Link

Bioproduction of Propionic Acid using Levulinic Acid by Engineered Pseudomonas putida. Tiwari R & Lee SK. Frontiers in Bioengineering and Biotechnology. Link

Biosensors

↑*Computational design of a sensitive, selective phase-changing sensor protein for the VX nerve agent. McCann JJ…Koder RL. Science Advances. Link

Circuits

*Transcriptional programming in a Bacteroides consortium. Huang BD, Groseclose TM & Wilson CJ. Nature Communications. Link

*Programmable synthetic cell networks regulated by tuneable reaction rates. Zambrano A…Tang T-YD. Nature Communications. Link

Computational Tools & Models

Validated In Silico Population Model of Escherichia coli. Rajagopal S…Datta S. ACS Synthetic Biology. Link

↑*A versatile active learning workflow for optimization of genetic and metabolic networks. Pandi A…Erb TJ. Nature Communications. Link

*Reconstruction of a catalogue of genome-scale metabolic models with enzymatic constraints using GECKO 2.0. Domenzain I…Nielsen J. Nature Communications. Link

*Protein–protein interaction and non-interaction predictions using gene sequence natural vector. Zhao N…Gong X. Communications Biology. Link

CRISPR & Central Dogma

*Highly efficient CRISPR-mediated large DNA docking and multiplexed prime editing using a single baculovirus. Aulicino F…Berger I. Nucleic Acids Research. Link

*A modular dCas9-based recruitment platform for combinatorial epigenome editing. Swain T…Lister R. bioRxiv (preprint). Link

Programmable Transcriptional Modulation with a Structured RNA-Mediated CRISPR-dCas9 Complex. He M…Liang H. JACS. Link

*EasyGuide plasmids support in vivo assembly of gRNAs for CRISPR/Cas9 applications in Saccharomyces cerevisiae. Jacobus AP…Gross J. bioRxiv (preprint). Link

Medicine & Diagnostics

↑*Generation of a live attenuated influenza A vaccine by proteolysis targeting. Si L…Plebani R. Nature Biotechnology. Link

*†Therapeutic in vivo delivery of gene editing agents. Raguram A, Banskota S & Liu DR. Cell. Link

*Low-cost anti-mycobacterial drug discovery using engineered E. coli. Bongaerts N…Wintermute EH. Nature Communications. Link

Intracerebral lentiviral ABCD1 gene therapy in an early disease onset ALD mouse model. Gong J…Chang L-J. Gene Therapy. Link

*Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism. Koh E…Chang MW. Nature Communications. Link

*A precise gene delivery approach for human induced pluripotent stem cells using Cas9 RNP complex and recombinant AAV6 donor vectors. Chupradit K…Wattanapanitch M. PLOS ONE. Link

Identification of RPGR ORF15 mutation for X-linked retinitis pigmentosa in a large Chinese family and in vitro correction with prime editor. Lv X…Gu F. Gene Therapy. Link

*Healthy cloned offspring derived from freeze-dried somatic cells. Wakayama S…Wakayama T. Nature Communications. Link

*Transplanted organoids empower human preclinical assessment of drug candidate for the clinic. Westerling-Bui AD…Mundel P. Science Advances. Link

Selective attachment of a microtubule interacting peptide to plasmid DNA via a triplex forming oligonucleotide for transfection improvement. Girardin C…Midoux P. Gene Therapy. Link

Plants

Synthetic memory circuits for stable cell reprogramming in plants. Lloyd JPB…Lister R. Nature Biotechnology. Link

*Diagnostics of Infections Produced by the Plant Viruses TMV, TEV, and PVX with CRISPR-Cas12 and CRISPR-Cas13. Marqués M-C…Rodrigo G. ACS Synthetic Biology. Link

*Producing fluorescent plants to lure and trap insect pests. Peng Q…Ning G. Plant Biotechnology Journal. Link

*CRISPR-Cas9-mediated mutagenesis of kiwifruit BFT genes results in an evergrowing but not early flowering phenotype. Herath D…Varkonyi-Gasic E. Plant Biotechnology Journal. Link

*A paired-end whole-genome sequencing approach enables comprehensive characterization of transgene integration in rice. Xu W…Yang L. Communications Biology. Link

Protein & Molecular Engineering

*Co-optimization of therapeutic antibody affinity and specificity using machine learning models that generalize to novel mutational space. Makowski EK…Tessier PM. Nature Communications. Link

*Engineering of ultraID, a compact and hyperactive enzyme for proximity-dependent biotinylation in living cells. Kubitz L…Béthune J. Communications Biology. Link

High-Throughput Aminoacyl-tRNA Synthetase Engineering for Genetic Code Expansion in Yeast. Stieglitz JT & Van Deventer JA. ACS Synthetic Biology. Link

*Proteolytically Activated CRAC Effectors through Designed Intramolecular Inhibition. Jazbec V, Jerala R & Benčina M. ACS Synthetic Biology. Link

Tools & Technology

*A plasmid system with tunable copy number. Rouches MV…Lambert G. Nature Communications. Link

↑*A time-resolved, multi-symbol molecular recorder via sequential genome editing. Choi J…Shendure J. Nature. Link

*A luciferase prosubstrate and a red bioluminescent calcium indicator for imaging neuronal activity in mice. Tian X…Ai H-W. Nature Communications. Link

Light-activated tetrazines enable precision live-cell bioorthogonal chemistry. Liu L…Devaraj NK. Nature Chemistry. Link

Decoupling Growth and Production by Removing the Origin of Replication from a Bacterial Chromosome. Kasari M…Jõers A. ACS Synthetic Biology. Link

Miscellaneous

*†Recent advances in organoid engineering: A comprehensive review. Unagolla JM, Jayasuriya AC. Applied Materials Today. Link

*†Exploring standards for multicellular mammalian synthetic biology. Glykofrydis F & Elfick A. Trends in Biotechnology. Link

*Aion is a bistable anion-conducting channelrhodopsin that provides temporally extended and reversible neuronal silencing. Rodriguez-Rozada S…Wiegert JS. Communications Biology. Link


More soon,

— Niko

Twitter: @NikoMcCarty