About That Nature Protocells Paper

How I messed up twice in one day.

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I made two mistakes in one day last week, and I want to tell you about them.

It was Wednesday. I woke up early so that I could eat breakfast, turn on my computer, and watch the White House’s Bioeconomy Summit at 9:00 AM. (If you’re confused because I said “woke up early” and “9:00 AM” in the same sentence, don’t be — I like to work late and sleep in.)

So there I was, watching politicians talk about money and science and the dire threats posed by China (at one point, a panelist referred to ‘mNRA’ vaccines) and I am writing down everything they say. I thought it’d be nice to recap the Summit in a newsletter in case you didn’t have the time or energy to watch it. By about 10:30 AM, I finished writing and, shortly after, sent the newsletter.

About an hour later, I get a notification on Twitter (a rare occurrence).

"The U.S. bioeconomy will be worth between $4 and $30 trillion by the end of the decade. The entirety of U.S. GDP today is about $21 trillion." So we're predicting almost 10% gdp growth for the next decade?”

I pulled the numbers from a Schmidt Futures report. But in my hasty writing, I wrote “U.S. bioeconomy” instead of “global bioeconomy.” So much damn American patriotism was coursing through my veins after watching the Summit; my brain made a stupid mistake. Such is the danger in covering live events — quality can take a dip when speed is optimized.

I corrected the newsletter and moved on.

Later in the day, a new paper about protocells — cells built from ‘scratch’ — came out in Nature. “Wow,” I thought. “Two cool things about synthetic biology in a single day?” But my thought was hasty.

In the paper, researchers explain how they took E. coli and another type of bacteria, embedded them in microdroplets, and then destroyed the microbes. The thing left behind — a droplet filled with bacterial ‘guts’ — did many of the things that living cells do, like peptide and RNA synthesis.

Which…of course it did.

After all, if you put cells in an enclosed container and blow them up, all of their ribosomes, DNA, and RNAs are still floating there. They can still do everything that a normal cell can; they just don’t have a membrane. This is basically the same thing as taking a TX-TL cell-free system and enclosing it in an oil droplet.

But I didn’t think about this at the time. Instead, I briefly skimmed the abstract, was sufficiently swooned by its lofty rhetoric and high Lexile score, and tweeted something like, “Amazing progress on protocells…” followed by a brief overview of the study.

And then the responses came. “So, it’s TX-TL in a droplet? With *many* fancy made-up words,” wrote Howard Salis. “The visuals are nice. But sometimes, I think we need a SynBio version of @epigenetichulk to keep us all grounded.”

“The fancy-words-to-describe-normal-things count in this paper is very impressive,” said Tom Ellis.

They were both right, of course. Despite writing about flaws in academia and science publishing for a living, I had been swooned by a glossy journal — curse Nature and its 69.5 impact factor!

Just take a look at this sentence from the study’s introduction:

Here, to address this challenge, we developed a living material assembly process based on the capture and on-site processing of spatially segregated bacterial colonies within individual coacervate microdroplets for the endogenous construction of membrane-bounded, molecularly crowded, and compositionally, structurally and morphologically complex synthetic cells.

What does any of this actually mean? “On-site processing” = transcription and translation? “Molecularly crowded” = the norm for any cell on planet earth? Here’s my (essentially) equivalent, rewritten version; I’ve taken some creative liberties:

Here, to address this challenge, we developed a way to put some bacteria, enzymes, and chemicals in oil droplets to build semi-synthetic protocells that sorta do some things that resemble living organisms.

Perhaps my rewritten version is missing some details, but that’s the whole point. I’ve now read the entire paper in detail, and I think many of its experiments have already been done by others (though, perhaps, not in an exhaustive or encompassing way). At its core, this study shows how to get bacteria and their cytoplasmic contents into a droplet, how to cleave DNA and condense it into a nucleus-like structure, and then how to add living cells and some actin proteins to make the droplets wiggle a bit. (For a different take on the paper, see the Nature news coverage).

When the data in this paper are evaluated collectively, it feels a bit like fistfuls of spaghetti were thrown at a wall to see what sticks.

Many of the papers’ experiments have also already been done by others (some more than a decade ago). There’s this recent demonstration of synthetic cytoskeletons for protocells and this one, too, from 2012. Many studies have already shown how to build compartments inside protocells, too; see here and here — the latter is from the same last author as this Nature paper. Prior studies have also trapped E. coli inside nanoparticles. And there’s this massive review of how protocells can carry out gene expression, build proteins, and so forth. And here are the details on making E. coli cytoplasmic extract, and here is a paper that reconstituted actomyosin rings — part of the cytoskeleton — inside oil droplets.

All this to say: I regret using the phrase “Amazing progress” to describe this paper in a tweet. As a writer, I never want to hype science or assess work based on persuasive writing over experimental data. As far as advances go, that recent ex vivo ribosome biogenesis preprint is more compelling and, I’d say, more important for building synthetic cells. In this instance, I was swooned by lofty writing, and I should have taken the time to put everything into context before opening my (metaphorical) mouth on Twitter. I deleted my tweet — the social media equivalent of a retraction.

As a writer, I constantly feel pressure to be relevant, dramatic, or funny. Nobody has time to read anything that isn’t one of these things. Something that hits all three usually goes viral.

Why do I put my head down for hours and slog through the latest protein design paper from David Baker? Because it’s relevant, and I want to be smarter. Why do I read Retraction Watch every weekend? Because I love the drama of scientists getting caught doing bad things.

Substack is filled with many thousands of writers. I’d guess that anywhere from 1-5% are good, and I don’t necessarily put myself in that camp. I’d like to be in that camp, but writing is a cutthroat gig and only a few people actually grow an audience. In a saturated market, the overall tolerance for mistakes is extremely low. Publish too many errors or hype too many things that later fail, and people will stop caring about what you have to say. Your predictions and insights will fall on deaf ears, and that is — or should be — career suicide for a writer. Thanks for reading.

On to the Index. Here are the latest papers in synthetic biology and biotechnology that you might have missed.

Biotech Index

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

Basic Research

↑*Reconstitution of microtubule into GTP-responsive nanocapsules. Uchida N…Aida T. Nature Communications. Link

3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice. Guerrero A…Gil J. Nature Aging. Link

*Functional Comparison between Endogenous and Synthetic Notch Systems. Khamaisi B…Sprinzak D. ACS Synthetic Biology. Link

*An RNA aptamer that shifts the reduction potential of metabolic cofactors. Samuelian JS…Baum DA. Nature Chemical Biology. Link

*Evolutionary inference across eukaryotes identifies universal features shaping organelle gene retention. Giannakis K…Johnston IG. Cell Systems. Link

*A bacterial pan-genome makes gene essentiality strain-dependent and evolvable. Rosconi F…van Opijnen T. Nature Microbiology. Link

Biomanufacturing & Metabolic Engineering

*Unleashing the potential of noncanonical amino acid biosynthesis to create cells with precision tyrosine sulfation. Chen Y…Xiao H. Nature Communications. Link

*Kinetic compartmentalization by unnatural reaction for itaconate production. Ye D-y…Jung GY. Nature Communications. Link

†The bright frontiers of microbial metabolic optogenetics. Wegner SA, Barocio-Galindo RM & Avalos JL. Current Opinion in Chemical Biology. Link

*Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants. Wang Y…Hailes HC. Nature Communications. Link

†Artificial intelligence and machine learning applications in biopharmaceutical manufacturing. Rathore AS…Mishra S. Trends in Biotechnology. Link

*GAGE is a method for identification of plant species based on whole genome analysis and genome editing. Hao L…Song J. Communications Biology. Link


*Highly multiplexed selection of RNA aptamers against a small molecule library. Townshend B, Kaplan M & Smolke CD. PLOS One. Link

†Novel DNA nanoflower biosensing technologies towards next-generation molecular diagnostics. Sheng J…Chang K. Trends in Biotechnology. Link

†Portable biosensors for rapid on-site determination of cannabinoids in cannabis, a review. Harpaz D…Eltzov E. Biotechnology Advances. Link

Computational Tools & Models

*Layered feedback control overcomes performance trade-off in synthetic biomolecular networks. Hu CY & Murray RM. Nature Communications. Link

CRISPR-based Editing & Control

↑*Systematically attenuating DNA targeting enables CRISPR-driven editing in bacteria. Collias D…Beisel CL. bioRxiv (preprint). Link

*Synthetic biology tools for transcriptional activation and regulation of biosynthetic gene clusters in filamentous fungi (Thesis). Mózsik L. Link

*U-to-C RNA editing by synthetic PPR-DYW proteins in bacteria and human culture cells. Ichinose M…Gutmann B. Communications Biology. Link

*Plant mitochondrial RNA editing factors can perform targeted C-to-U editing of nuclear transcripts in human cells. Lesch E…Schallenberg-Rüdinger M. Nucleic Acids Research. Link

†The double life of CRISPR–Cas13. Bot JF, van der Oost J & Geijsen N. Current Opinion in Biotechnology. Link

DNA Storage

*Robust data storage in DNA by de Bruijn graph-based de novo strand assembly. Song L…Yuan Y-J. Nature Communications. Link

Environment & Climate

†The emerging potential of natural and synthetic algae-based microbiomes for heavy metal removal and recovery from wastewaters. Greeshma K, Kim H-S & Ramanan R. Environmental Research. Link

Gene Synthesis & Assembly

*†Approaches for bacteriophage genome engineering. Mahler M…Brouns SJJ. Trends in Biotechnology. Link

Genetic Circuits

Steady-State Operation of a Cell-Free Genetic Band-Detection Circuit. Jäkel AC, Aufinger L & Simmel FC. ACS Synthetic Biology. Link

*Yeast transcriptional device libraries enable precise synthesis of value-added chemicals from methanol. Zhu Q…Cai M. Nucleic Acids Research. Link

Medicine & Diagnostics

↑†Treatment of Genetic Diseases With CRISPR Genome Editing. Kan MJ & Doudna JA. JAMA Insights. Link

*Design of the SARS-CoV-2 RBD vaccine antigen improves neutralizing antibody response. Dickey TH…Tolia NH. Science Advances. Link

*A Bivalent Omicron-Containing Booster Vaccine against Covid-19. Chalkias S…Das R. The New England Journal of Medicine. Link

*Molecular engineering of a cryptic epitope in Spike RBD improves manufacturability and neutralizing breadth against SARS-CoV-2 variants. Rodriguez-Aponte SA…Love JC. bioRxiv (preprint). Link

*Therapeutic high affinity T cell receptor targeting a KRAS(G12D) cancer neoantigen. Poole A…Chillakuri C. Nature Communications. Link

*Exosome-mediated delivery of Cas9 ribonucleoprotein complexes for tissue-specific gene therapy of liver diseases. Wan T…Liu X. Science Advances. Link

†Intestinal Engineered Probiotics as Living Therapeutics: Chassis Selection, Colonization Enhancement, Gene Circuit Design, and Biocontainment. Huang Y…Chen W. ACS Synthetic Biology. Link

*†Protein scaffolds in human clinics. Cano-Garrido O…Vázquez E. Biotechnology Advances. Link

†Virus-like particles for drug delivery: a review of methods and applications. Ikwuagwu B & Tullman-Ercek D. Current Opinion in Biotechnology. Link

Microbial Communities

†SynMADE: synthetic microbiota across diverse ecosystems. Moon TS. Trends in Biotechnology. Link


*Reconstitution of monoterpene indole alkaloid biosynthesis in genome engineered Nicotiana benthamiana. Dudley QM…Patron NJ. Communications Biology. Link


Living material assembly of bacteriogenic protocells. Xu C…Mann S. Nature. Link

*A ubiquitous amino acid source for prokaryotic and eukaryotic cell-free transcription-translation systems. Nagappa LK…Moore SJ. Frontiers in Bioengineering and Biotechnology. Link

Protein & Molecular Engineering

↑Robust deep learning–based protein sequence design using ProteinMPNN. Dauparas J…Baker D. Science. Link

↑Hallucinating symmetric protein assemblies. Wicky BIM…Baker D. Science. Link

  • See also: From sequence to function through structure: deep learning for protein design by Ferruz N. et al on bioRxiv. Link
  • See also: Learning inverse folding from millions of predicted structures by Hsu C. et al. on bioRxiv. Link

*A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging. Wang L…Chu J. Nature Communications. Link

*Assembly of transmembrane pores from mirror-image peptides. Krishnan RS…Mahendran KR. Nature Communications. Link

Enzyme activity engineering based on sequence co-evolution analysis. Kim D…Kim S. Metabolic Engineering. Link

Stem Cells, Tissues & Organs

↑*Optogenetic control of apical constriction induces synthetic morphogenesis in mammalian tissues. Martínez-Ara G…Ebisuya M. Nature Communications. Link

†Ethical challenges with 3D bioprinted tissues and organs. Datta P…Ozbolat IT. Trends in Biotechnology. Link

Implanted synthetic cells trigger tissue angiogenesis through de novo production of recombinant growth factors. Chen G…Schroeder A. PNAS. Link

Tools & Technology

*An ultra high-throughput, massively multiplexable, single-cell RNA-seq platform in yeasts. Brettner L…Geiler-Samerotte K. bioRxiv (preprint). Link

*Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing. Simmons SK…Levin JZ. Nature Biotechnology. Link

*Development of a High-Performance Open-Source 3D Bioprinter. Tashman JW, Shiwarski DJ & Feinberg AW. bioRxiv (preprint). Link


*The phenotypic plasticity of an evolving digital organism. Fortuna MA. Royal Society Open Science. Link

*A droplet-based microfluidic platform enables high-throughput combinatorial optimization of cyanobacterial cultivation. Cao J…Zedler JAZ. Scientific Reports. Link

Cultivation of previously uncultured microorganisms with a continuous-flow down-flow hanging sponge (DHS) bioreactor, using a syntrophic archaeon culture obtained from deep marine sediment as a case study. Imachi H…Takai K. Nature Protocols. Link

*Metal Ion- Directed Coordination Programming of Biomolecules to Bioinspired Nanoflowers. Butreddy P, Holden H & Rathnayake H. Macromolecular Chemistry and Physics. Link

More soon,

— Niko

Twitter: @NikoMcCarty