In the summer of 2020, I was living in a closet-sized apartment (and paying $2,650 each month for the privilege) in New York City’s Lower East Side. I spent my cramped weekends scouring the Internet for research papers and pasting them into this newsletter. Eventually, I began to write longer essays, too, and the newsletter slowly grew in size. I never imagined that my weekend hobby would ever become my full-time career. But now it has. 

Starting today, Codon is officially part of Asimov Press, an editorially-independent publishing venture modeled on Stripe Press. Asimov Press will produce a newsletter, magazine, and books that feature writing about biology, and I’m honored to be leading it with my colleague, Xander Balwit. 

We’ll publish at least one article every two weeks, with additional newsletters and shorter essays scattered in-between. These articles will be much like the essays I’ve published here on Codon in the past, except they will be much deeper (and better) because we have a budget to pay writers, hire artists, and edit.

We are generously funded by Asimov, but will not publish anything about the company or its commercial interests. (I usually roll my eyes when people say, “I swear our funders have no say in what we publish!” but our articles will attest to this.) Writing essays, and helping others to do the same, is now my career. This is a dream come true.

Asimov Press will publish long-form deep dives on everything from biosecurity to vaccine development, in addition to speculative fiction that imagines positive, plausible visions of the future. Photo essays and book projects will launch in 2024. Our pitch guide is available online. Follow us, if you’d like, on Twitter and LinkedIn.

If you received this email, that means you’re already subscribed. The next email you see (starting tomorrow) will be from Asimov Press. Please stay and join us. If you’d prefer to unsubscribe, click the link at the end of this email. Now for some FAQs:

1. Is this newsletter still about biotechnology?

   1. Yes. But we’ll publish higher quality work, more consistently. Asimov Press has received 450+ pitches to-date and we’ve commissioned about 10 essays. We’re really excited to share them with you soon, in addition to the magazine and book projects.

2. Are you selling out?

   1. Believe it or not, I received $0 in compensation for this – no cash or equity. But the transition makes sense: Asimov Press takes up most of my time, which means I don’t have as much time to write essays for Codon. Why not unite my day job and my hobby and just spend 100% of my time writing and editing the best pieces that I can possibly manage?

3. Will you start publishing different types of pieces?

   1. Maybe a bit. Asimov Press is hyper-focused on biology and science, so there won’t be any pieces like “how to write on the internet.” The pieces will also be more professional; many contributors are published book authors or serial writers. I’ll continue to write articles for Asimov Press and elsewhere. 

Other Updates:

In October, I announced a new writing fellowship, called Ideas Matter, together with Pillar VC and Homeworld Collective. We received more than 520 applications and selected 14 fellows for the inaugural cohort. Fellows will spend 8 weeks developing articles about biosecurity, placebos, animal welfare, and other timely topics in biology. (MORE BIOLOGY WRITERS = GOOD THING! ) We’ll share updates on Twitter, LinkedIn, and our website.

The writing challenge, announced way back in August, has also wrapped up. We received about 150 submissions. Homeworld & Pillar will distribute $12,950 in cash prizes. Each submission was reviewed by at least three judges, and all the winners have been notified. Thanks to everyone who wrote a piece, more than half of whom said, in a survey, that they wouldn’t have done so without this competition! (Huge win.) A formal announcement is forthcoming.

And finally, thanks to you for joining me on this journey over the last 3+ years! I hope you have a beautiful holiday with friends and family. Here’s to the years ahead.

- Niko

I. Moonshots

Physics was long dominated by solitary celebrities. Newton formulated laws of motion, Einstein developed a theory of relativity, and Dirac sculpted a general theory of quantum mechanics. 

But then, World War II changed the equation. The Manhattan project employed 130,000 people and cost $2.2 billion, or more than $25 billion in today’s dollars. As money poured into wartime research programs, physics shifted from a field of brilliant individuals to one of well-managed teams. Sure, there are still solitary celebrities (Sagan, Hawking, and Thorne), but great discoveries today seem to stem mostly from large programs with multi-billion dollar price tags.

The Higgs boson was discovered at CERN, a sprawling particle physics laboratory that cost more than $10 billion to build. LIGO, which detects gravitational waves via tiny fluctuations in laser beams, cost more than $1 billion. The James Webb Space Telescope, Hubble’s successor, cost nearly $10 billion to construct. Biology has had a few large-scale research programs, such as the Human Genome Project, but nowhere near the same number as physics. Why not?

There are a few reasons. For one, biology research is inherently broad. A zoologist, ecologist, and protein engineer all call themselves “biologists,” but rarely attend the same conferences. Biological discoveries are made organically, with thousands of teams chipping away at niche problems until one, or a handful of groups, strike gold. And biology research is opaque; research teams don’t share their results until a paper is published. All these quirks make it difficult to coordinate on large problems. 

Natural science can learn a great deal from physics, where progress is made by proposing new models and then demonstrating their veracity through experiments. Einstein predicted the existence of gravitational waves in 1916, but LIGO did not detect them until 2015. Katherine Johnson calculated a flight path to send humans to the moon in 1962, based on the mechanics that Newton devised in 1678.

The foundation of physics has been built over several centuries, thanks to a constant back-and-forth dialogue between theory and experiment. Progress in biology will similarly accelerate once the field builds predictive models that can accurately anticipate the outcome of experiments before they have taken place.

The transformation has already begun. Consider AlphaFold2, a model that predicts protein structures with an accuracy that matches or exceeds experimental methods. It was the first computational method to “regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known,” according to the study in Nature. AlphaFold2 was important not only for its structure predictions, but because it was the first model in the history of the life sciences that reduced the number of experiments biologists perform.

So why stop there? AI capabilities are growing rapidly, and now is the time to develop broader predictive models that can provide answers to unanswered questions at every size scale of biology: from molecules, to whole cells, to the behavior of cells at the macroscale. But to make those models a reality, biologists will first need to learn from physics.

II. Predictive Models

A “sequence-to-function” predictive model – an algorithm that determines a protein’s likely function solely by looking at the DNA sequence encoding it – is the natural successor to AlphaFold2. Such a model would make it possible to discover protein functions by scraping metagenomic databases, or to create proteins with functions that exist nowhere in nature.

A training dataset for a sequence-to-function model needs just three variables: Amino acid sequence, a quantitative functional score (a number that reflects how well the protein performs when tested in an experiment), and function-definition, or a rigorous description of the experiment used to benchmark what the protein does. This last variable could be just about anything; there are proteins that bind to other proteins (like antibodies), cut other proteins (proteases), or bind DNA (transcription factors). 

Roughly a dozen sequence-to-function datasets already exist (see Supplemental Table 1 in this 2022 study), each with more than five thousand data points. But even if all these datasets were combined, they still wouldn’t have anywhere near enough data to build a cursory predictive model. 

Align to Innovate’s Open Datasets Initiative (one of us, Erika DeBenedictis, is the founder) roadmaps high-impact datasets in biology, and then hires automation engineers to collect them. They are building an expansive sequence-to-function dataset by running pooled, growth-based assays: First, hundreds of thousands of gene variants are synthesized and then added to a cell. Then, the activity of each gene variant is linked to a cell’s ability to grow, and the cells are cultured in a tube. A few hours later, cellular abundances are measured and growth is used as a proxy for each protein’s function. Robots can test 100,000+ variants, in one tube, for less than $0.05 per protein. 

A predictive model for protein function would be revolutionary, but most useful if the proteins that it creates actually express in living cells.

Large-scale experiments suggest that <50% of bacterial proteins and <15% of non-bacterial proteins express within E. coli in a soluble form, and these low “hit” rates slow progress. This is the reason why many biologics — medicines made by, or extracted from, living cells — don’t make it to market. A predictive model for sequence-to-expression would raise the “hit” rates.

Recent experiments have quantified protein expression levels for thousands of protein mutants in a single experiment, so it’s definitely possible to collect large datasets to train such a predictive model. Also, codon optimizers today can tweak gene sequences to boost the odds that they will express in E. coli, yeast, and other types of organisms. Codon optimizers have effectively solved one part of protein expression; augmenting them with additional data on protein stability, pH, salt, temperature, chaperones, proteases, and other factors unique to each cell’s internal environment could plausibly be used to build the first true sequence-to-expression model. 

A training dataset could be built by expressing billions of proteins in industrially relevant microbes, such as E. coli, B. subtilis, and P. pastoris. These data would then be used to train a model that predicts expression as a function of a language model embedding. With the basic experimental structure in place, the dataset could then be expanded to handle more proteins, or more diverse cell types.

The biggest challenge will be to acquire DNA that encodes millions of different proteins. Synthesizing that much DNA is cost-prohibitive. If you have protein libraries in your research laboratory, please send them to us (datasets@alignbio.org) for analysis. We’ll analyze the proteins and provide you with expression data for free. We’re especially interested in sequence-diverse proteins from microbes, such as metagenomic libraries. More community involvement, and more DNA, will ultimately boost the predictive capabilities of the final model. 

Even with predictive models for protein function and expression in hand, biologists are still hamstrung by the types of organisms that can be handled in the laboratory. The hypothetical dream is for biologists to express any protein, with any function, in any organism. The final scale for a predictive model, then, is sequence-to-growth; biologists should build an algorithm that can infer the optimal growth nutrients for any microbe, solely by looking at its genome sequence. This is likely the hardest model to train, but its impacts would be huge.

Theodor Escherich, a bearded physician in Austria, was first to isolate E. coli (from his own feces) in 1885. So really, what are the odds that this is the end-all be-all microbe for scientific progress? E. coli may have “unexhausted potential” as a model organism (it was studied in nearly 15,000 biomedical research papers in 2022 alone), but there are other microbes that grow in hydrothermal vents, or survive in the vacuum of space, that have fascinating mechanisms for biologists to exploit.

A sequence-to-growth model would broaden the organisms used in biology. It would make it possible to concoct an “optimal broth” to grow a greater number of organisms. Small models can already tackle a modest version of this problem, but it’ll be a tall order to collect enough data to build a broadly general model. Cells are basically bags of 10¹³ interacting components immersed in a chaotic environment; deciphering how these conditions control an organism’s growth is an intellectually intriguing – but puzzling – challenge.

III. Lift Off

The data used to train Alphafold2 cost an estimated $10 billion to collect, and was made possible thanks to a relentless generation of crystallographers who solved tens of thousands of protein structures and uploaded them to public databases.

The paradox in building further models that reduce our reliance on experiments “lies in the fact that, to escape the limitations of wet lab screens, one must, in fact, run more wet lab assays to build out model performance,” according to Lada Nuzhna and Tess van Stekelenburg in Nature Biotechnology. In other words, reducing biology’s reliance on wet-lab experiments requires, first, that biologists perform many more wet-lab experiments. And that will prove challenging for two reasons.

First, biology suffers from scale. The magnitude of data required to build accurate models exceeds the financial limits of any single laboratory. And second, biology experiments don’t always replicate. Each laboratory collects data in slightly different ways, and it’s often challenging to reconcile data between them.

But many groups are now working toward predictive models. There has been progress. In September, the Chan Zuckerberg Initiative announced a new computing cluster, with more than 1,000 GPUs, that would “provide the scientific community with access to predictive models of healthy and diseased cells.” Oak Ridge National Laboratory has an entire team working on predictive biology, and Huimin Zhao at the University of Illinois is leading an effort to use a biological foundry, with three liquid-handling robots, to collect data that will train a predictive model for enzyme function.

In the coming decades, we may actually see predictive models that help biologists express any protein, with any function, in any organism. Such a feat would be incredible, considering that biology research today resembles manufacturing before the industrial revolution: many small craftsmen, each creating hand-made products, through bespoke processes.

The artisanal nature of biology research slows down progress. Researchers are constantly reinventing techniques. Collected datasets are usually modest in size, and gathering more data ‘the same way’ is not always possible because the protocol may not “work in your hands”. Artisanal biology is beautiful, but also going nowhere fast.

Even five years ago, unifying models of biology sounded like a pipe dream. Most scientists were craving models that had the same theoretical certainty and interpretability of the mathematical proofs that guide physics and computer science. Instead, the marriage of large datasets and machine learning may pave the way for biology to mature into a predictable engineering discipline without full interpretability. Practically speaking, whatever sort of math is under the hood, any predictive model that is as good as experiment creates a foundation on which more complex understanding can be built. Predictive biology models have the potential to place the field on solid footing for the first time in history.

Whereas the last century of biology looked like an organic and exploratory process, with many small groups discovering and rediscovering curiosities, the next century will resemble a coordinated, whole-field effort to divide biology into a series of prediction tasks and then solve those tasks, one-by-one.

Erika DeBenedictis is a computational physicist and molecular biologist at the Francis Crick Institute in London, and the founder of Align to Innovate, a nonprofit working to improve life science research through programmable experiments.

Niko McCarty is a writer and former synthetic biologist. He’s a founding editor at Asimov Press, co-founder of Ideas Matter, and is a genetic engineering curriculum specialist at MIT.

Please send questions and feedback to contact@alignbio.org. Thanks to Pete Kelly, Dana Cortade, TJ Brunette and Carrie Cizauskas for reading drafts of this piece.

Great stories have the power to change minds, build teams, and raise money. An ironclad argument, with an enticing hook and rigorous thesis, can form the basis of radical new companies. (The act of writing itself will help you live more curiously.) And yet, schools rarely teach the art of storytelling, or explain how to harness the power of the Internet to catalyze a career.

Last month, I co-launched a writing contest, Homeworld Ideas, with my friends at Homeworld Collective and Pillar VC. Our goal was to encourage more people to write on the Internet by offering cash incentives. (Submissions are open until October 15th.) Many people told us that the competition motivated them to put effort into writing when they hadn’t for a long time. This was encouraging, but we know we can do more.

Today, we’re launching Ideas Matter, an intensive, 8-week writing fellowship that helps current — and aspiring — science writers craft stories that resonate with a wider audience, mainly through blogs, essays, and newsletters. This program was again co-created with Pillar VC and Homeworld Collective.

Ideas Matter Fellows will write two edited pieces for inclusion in a published anthology. They will join a selective writing community and gain access to a pot of funds to hire professional editors and artists, or to take reporting trips. The fellowship is online, anyone is welcome to apply, and the application takes less than 10 minutes to complete. Our first cohort will be focused on writing about biology and will run from January 8th to March 1st, 2024.

Apply Here

Fellows will meet with expert writers and editors each week. Guests will teach the art of finding great ideas, explain how to convert “nebulous thoughts” into ironclad stories, and coach fellows on growing an audience. Our deepest gratitude goes to:

• Nick Lane, author of The Vital Question, Transformer, and other books; professor at University College London.

• Saloni Dattani, researcher on global health at Our World in Data; founding editor at Works in Progress magazine.

• Ed Boyden, professor of synthetic neurobiology at MIT; former columnist at MIT Technology Review.

• Christina Agapakis, Creative Director of Ginkgo Bioworks; executive editor of Grow magazine.

• Elliot Hershberg, biotech partner at Not Boring; writer at The Century of Biology.

• Alexey Guzey, writer; founder of New Science; consultant at OpenAI.

• Eli Dourado, senior research fellow at the Center for Growth and Opportunity at Utah State University; writer.

• Emily Mullin, staff writer at WIRED, covering biotechnology.

We’ll announce additional speakers in the coming weeks. Our focus on biology, at least for this first cohort, is deliberate. 

This century will be transformed by humanity’s ability to understand, control, and harness biology for the climate, medicine, and manufacturing. In 2022, the U.S. bioeconomy was valued at $950 billion, or roughly 5% of GDP. As gene-editing and predictive models accelerate its growth, writing about biology has been — at times — shallow, overhyped, or misunderstood. We need to train an entire generation of biology writers who can make sense of this century of progress.

Our focus on biology won’t last forever, though. In future fellowships, we’ll work with writers in machine learning, climate, and other subfields. We are focusing on one field at a time because beautiful friendships emerge when a group of people with similar backgrounds, ideas and desires (“biology is amazing”) work toward a common goal (“become a better writer”). We also want every fellow to feel like they can comment on, and improve, the writing of every other fellow.

A handful of writing fellowships have emerged in recent years, but we’re not aware of any for science writing. Roots of Progress, however, has already proven that specialized writing fellowships are both possible and can be wildly popular — they received nearly 500 applications for 20 fellowship slots.

Internally, our team likes to say that this fellowship is an early experiment toward a sort of “Y Combinator for Writers.”

Can a bit of money, combined with lots of time and thoughtful community-building, foster an entire generation of writers who seed ideas, push scientific fields in new directions, or build the companies, non-profits, and research laboratories that will lead us into the future? We think so.

If you’re excited about this vision, please apply.

Apply Here

Thanks to Tony Kulesa, Madelyn Heart, Katie Okolita, Daniel Goodwin and Paul Reginato for making this possible.

Writing is a way to will ideas into the world. A good idea — presented clearly, backed by evidence, and packaged in a story — can help you raise money for a cause, rally people to an idea, or shift the directions of a field.

But too many promising ideas are filed away on dusty hard drives, doomed to an eternity of damp, cardboard boxes. And that’s a real shame. More people should share their ideas in public. Public feedback strengthens ideas, and hitting “send” is often the defining step to make an idea feel tangible or actionable.

I want more people to publish their ideas in the open. I want to read more essays about biology. I want to see blog posts become the foundation of new companies. I want to help elevate people with good ideas, especially those outside the ivory tower, in the ivory foothills.

That’s why, today, we’re announcing Homeworld Ideas, a $12,500 writing challenge that invites you to share your visions for how biology can enable a positive and more sustainable future. I’m co-leading this with my friends at Homeworld Collective, a climate biotechnology nonprofit. Runners-up prizes are generously provided by Pillar VC.

Anyone can submit a piece in just about any format – poetry, essays, reportage, science fiction, book chapters, and so on. We’ll give away a $10,000 top prize and $2,500 in additional prizes. We’ll also take the best submissions, publish them online, and share them in this newsletter. You can enter up to three pieces (including work you’ve already published), pseudonyms are okay, and the deadline is October 15th. Please send questions to writing@homeworld.bio.

Click here for more details, and here to apply.

To be honest, this writing challenge is an experiment. I hope lots of people submit pieces, but I don’t know what’s going to happen. Our hypothesis is that money and marketing (from myself, Homeworld, and Pillar) will incentivize people to share their work and also boost the signal-to-noise ratio of good ideas. But we can’t test this hypothesis without you.

To encourage you to enter, let’s consider a few essays that tangibly bent the arc of a person’s life.

Alexey Guzey’s “How Life Sciences Actually Work” helped him raise money to start a non-profit. Adam Green wrote a brilliant blog, “A Future History of Biomedical Progress,” that helped him start an AI drug discovery company. My friend, Dan Goodwin, wrote a blog called, “What are the most productive communities?” that was read by donors who later helped him co-found Homeworld Collective. Matt Faherty wrote a long report about problems with the National Institutes of Health (that I edited), which was later cited by the House of Representatives’ Committee on Energy and Commerce.

All this to say: Give it a shot. If you have a good idea on your hard drive, or stored in a cardboard box somewhere, send it to us. If there’s an idea you’ve been meaning to write down, now is the best time to do it.

If all goes well, this will be the first of many writing challenges, and hundreds of voices will contribute ideas to the radical blossoming of our biological future. We’re excited to read your work.

Last edit: 13 September 2023

Progress in biology is arguably moving faster today than at any point in the course of human history. Engineered biology has profound potential to change how we live, but the field has become broad, bloated, nebulous. It can feel overwhelming just to keep up, let alone enter the subject, grasp its core ideas, or contribute to its improvement.

The first step to mastering a subject is to start…somewhere. And the best way to find that somewhere, often, is with a guide. So I spent the last week scouring the web and racking my brain for useful resources on synthetic biology. Consider this your “start” on a (hopefully) long and fulfilling intellectual journey.

This guide is a living document. Please send suggestions and additions to my email. I gratefully acknowledge others who have compiled similar resources, including Michael Retchin, Roberto Solari, Alex Telford, and Pillar VC.

📙 Seminal Papers to Get You Up to Speed

Mostly open-access; some are paywalled. → means “start here.”

Foundations

Basics of Synthetic Biology

→Foundations for engineering biology, by Endy D. Nature (2005). Link
→A brief history of synthetic biology, by Cameron D.E. et al. Nature Reviews Microbiology (2014). Link
Synthetic biology: applications come of age, by Khalil A.S. & Collins J.J. Nature Reviews Genetics (2010). Link
Is the cell really a machine?, by Nicholson D.J. Journal of Theoretical Biology (2019). Link
The second wave of synthetic biology: from modules to systems, by Purnick P.E.M. & Weiss R. Nature Reviews Molecular Cell Biology (2009). Link
The second decade of synthetic biology: 2010–2020, by Meng F. & Ellis T. Nature Communications (2020). Link
Synthetic biology in mammalian cells: next generation research tools and therapeutics, by Lienert F. et al. Nature Reviews Molecular Cell Biology (2014). Link

The Central Dogma

→60 years ago, Francis Crick changed the logic of biology, by Cobb M. PLoS Biology (2017). Link
The Elaboration of the Central Dogma. Scitable, by Nature Education. Link
Central dogma at the single-molecule level in living cells, by Li G-W. & Xie X.S. Nature (2011). Link

Gene Expression & Regulation

→Genetic regulatory mechanisms in the synthesis of proteins, by Jacob F. & Monod J. Journal of Molecular Biology (1961). Link (Explained).
Gene Expression and Regulation. Scitable, by Nature Education. Link
A Unified Theory of Gene Expression, by Orphanides G. & Reinberg D. Cell (2002). Link
Precise and reliable gene expression via standard transcription and translation initiation elements, by Mutalik V.K. et al. Nature Methods (2013). Link

Biological Networks & Mathematics

→Network motifs in the transcriptional regulation network of Escherichia coli, by Shen-Orr S.S. et al. Nature Genetics (2002). Link
Modelling and analysis of gene regulatory networks, by Karlebach G. & Shamir R. Nature Reviews Molecular Cell Biology (2008). Link
Artificial Gene Regulatory Networks—A Review, by Cussat-Blanc S. et al. Artificial Life (2018). Link
Mathematical modeling and synthetic biology, by Chandran D. et al. Drug Discovery Today: Disease Models (2008). Link

Graphic Notations

→Synthetic Biology Open Language Visual: An Open-Source Graphical Notation for Synthetic Biology, by Quinn J. et al. Link
The Synthetic Biology Open Language (SBOL) provides a community standard for communicating designs in synthetic biology, by Galdzicki M. et al. Nature Biotechnology (2014). Link
The Systems Biology Graphical Notation, by Le Novère N. et al. Nature Biotechnology (2009). Link

Technologies

DNA Sequencing

→DNA sequencing at 40: past, present and future, by Shendure J. Nature (2017). Link
DNA Cost and Productivity Data, aka "Carlson Curves", by Carlson R. Synthesis.cc (2022). Link
Next-Generation DNA Sequencing Methods, by Mardis E.R. Annual Review of Genomics and Human Genetics. (2008). Link

DNA Synthesis

→Large-scale de novo DNA synthesis: technologies and applications, by Kosuri S. & Church G.M. (2014). Link
DNA synthesis technologies to close the gene writing gap, by Hoose et al. (2023). Link
Synthetic DNA Synthesis and Assembly: Putting the Synthetic in Synthetic Biology, by Hughes R.A. & Ellington A.D. Cold Spring Harbor Perspectives in Biology. Link
Deoxynucleoside phosphoramidites—A new class of key intermediates for deoxypolynucleotide synthesis, by Beaucage S.L. & Caruthers M.H. Tetrahedron Letters (1981). Link
Synthesis of high-quality libraries of long (150mer) oligonucleotides by a novel depurination controlled process, by LeProust E.M. et al. Nucleic Acids Research (2010). Link
De novo DNA synthesis using polymerase-nucleotide conjugates, by Palluk S. et al. Nature Biotechnology (2018). Link

DNA Assembly

→Bricks and blueprints: methods and standards for DNA assembly, by Casini A. et al. Nature Reviews Molecular Cell Biology (2015). Link
Recent advances in DNA assembly technologies, by Chao R. et al. FEMS Yeast Research (2015). Link
BglBricks: A flexible standard for biological part assembly, by Anderson J.C. et al. Journal of Biological Engineering (2010). Link
Enzymatic assembly of DNA molecules up to several hundred kilobases, by Gibson D.G. et al. Nature Methods (2009). Link (Gibson assembly)
A Modular Cloning System for Standardized Assembly of Multigene Constructs, by Weber E. et al. PLoS One. (2011). Link (Golden Gate assembly) 

Other Basic Methods & Cloning

→Basic Methods in Cellular and Molecular Biology, by multiple authors. JoVE. Link
→DNA cloning: A personal view after 40 years, by Cohen S.N. PNAS (2013). Link
Molecular Cloning Techniques, by AddGene. Link
Isolating, Cloning, and Sequencing DNA, by Alberts B. et al. Molecular Biology of the Cell, 4th Edition. Link

CRISPR-Cas

→CRISPR-Cas: biology, mechanisms and relevance, by Hille F. & Charpentier E. Philosophical Transactions of the Royal Society B (2016). Link
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, by Jinek M. et al. (2012). Link
CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity, by Chen J.S. et al. Science (2018). Link
Nucleic acid detection with CRISPR-Cas13a/C2c2, by Gootenberg J.S. et al. Science (2017). Link
The next generation of CRISPR–Cas technologies and applications, by Pickar-Oliver A. & Gersbach C.A. (2019). Link

Base Editing

→Base editing: precision chemistry on the genome and transcriptome of living cells, by Rees H.A. & Liu D.R. (2018). Link
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage, by Komor A.C. et al. (2016). Link
Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage, by Gaudelli N.M. et al. (2017). Link

Prime Editing

→Prime editing for precise and highly versatile genome manipulation, by Chen P.J. & Liu D.R. Nature Reviews Genetics. (2022). Link
Search-and-replace genome editing without double-strand breaks or donor DNA, by Anzalone A.V. et al. (2019). Link

Directed Evolution

→Exploring protein fitness landscapes by directed evolution, by Romero P.A. & Arnold F.H. Nature Reviews Molecular Cell Biology (2009). Link
Tuning the activity of an enzyme for unusual environments: sequential random mutagenesis of subtilisin E for catalysis in dimethylformamide, by Chen K. & Arnold F.H. PNAS (1993). Link
Methods for the directed evolution of proteins, by Packer M.S. & Liu D.R. Nature Reviews Genetics (2015). Link

Protein Structure Prediction & Design

→Advances in protein structure prediction and design, by Kuhlman B. & Bradley P. Nature Reviews Molecular Cell Biology (2019). Link
→A Brief History of De Novo Protein Design: Minimal, Rational, and Computational, by Woolfson D.N. Journal of Molecular Biology (2021). Link
The coming of age of de novo protein design, by Huang P-S. et al. Nature (2016). Link
Highly accurate protein structure prediction with AlphaFold, by Jumper J. et al. Nature (2021). Link (See the blog by Mohammed AlQuraishi.)

Genome Synthesis

→Synthetic Genomes, by Zhang W. et al. Annual Review of Biochemistry (2020). Link
Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome, by Gibson D.G. et al. Science (2010). Link
One-step assembly in yeast of 25 overlapping DNA fragments to form a complete synthetic Mycoplasma genitalium genome, by Gibson D.G. et al. PNAS (2008). Link
Construction of a synthetic Saccharomyces cerevisiae pan-genome neo-chromosome, by Kutyna D.R. et al. Nature Communications (2022). Link (See this blog about the synthetic yeast project.)
Design and synthesis of a minimal bacterial genome, by Hutchison C.A. et al. Science (2016). Link
Defining synonymous codon compression schemes by genome recoding, by Wang K. et al. Nature (2016). Link

Applications

Biomaterials

→The living interface between synthetic biology and biomaterial design, by Liu A.P. et al. Nature Materials (2022). Link
Biological Engineered Living Materials: Growing Functional Materials with Genetically Programmable Properties, by Gilbert C. & Ellis T. ACS Synthetic Biology. Link
Wearable materials with embedded synthetic biology sensors for biomolecule detection, by Nguyen P.Q. et al. Nature Biotechnology (2021). Link
Regulating synthetic gene networks in 3D materials, by Deans T.L. et al. PNAS (2012). Link

Biosecurity & Biocontainment

→Building biosecurity for synthetic biology, by Trump B.D. et al. Molecular Systems Biology (2020). Link
Mitigating catastrophic biorisks, by Esvelt K. Effective Altruism. Link
Rational Design of Evolutionarily Stable Microbial Kill Switches, by Stirling F. et al. Molecular Cell (2017). Link
Synthetic biology approaches to biological containment: pre-emptively tackling potential risks, by Torres L. et al. Essays in Biochemistry (2016). Link
Benchtop DNA printers are coming soon—and biosecurity experts are worried, by Service R.F. Science (2023). Link
Biocontainment of genetically modified organisms by synthetic protein design, by Mandell D.J. et al. Nature (2015). Link
What rough beast? Synthetic biology, uncertainty, and the future of biosecurity, by Mukunda G. et al. Politics and the Life Sciences (2009). Link

Biosensors

→Synthetic Biology Enables Programmable Cell-Based Biosensors, by Hicks M. et al. ChemPhysChem (2019). Link
Cell-free biosensors for rapid detection of water contaminants, by Jung J.K, et al. Nature Biotechnology (2020). Link
Arsenic biosenseor: a step further, by French C. et al. BMC Systems Biology (2007). Link
Paper-Based Synthetic Gene Networks, by Pardee K. et al. Cell (2014). Link

Cell-Free Systems

→Synthetic Biology Goes Cell-Free, by Tinafar A. et al. BMC Biology (2019). Link
Cell-free gene expression, by Garenne D. et al. Nature Reviews Methods Primers (2021). Link
Cell-free gene expression: an expanded repertoire of applications, by Silverman A.D. et al. Nature Reviews Genetics (2019). Link
The PURE system for the cell-free synthesis of membrane proteins, by Kuruma Y. & Ueda T. Nature Protocols (2015). Link
An integrated cell-free metabolic platform for protein production and synthetic biology, by Jewett M.C. et al. Molecular Systems Biology (2008). Link
In vitro integration of ribosomal RNA synthesis, ribosome assembly, and translation, by Jewett M.C. et al. Molecular Systems Biology (2013). Link
Portable, On-Demand Biomolecular Manufacturing, by Pardee K. et al. Cell (2016). Link

Gene Circuits

→Principles of genetic circuit design, by Brophy J.A.N. & Voigt C.A. (2014). Link
Understanding Biological Regulation Through Synthetic Biology, by Bashor C.J. & Collins J.J. (2018). Link
Designing Biological Circuits: Synthetic Biology Within the Operon Model and Beyond, by English M.A. et al. Annual Review of Biochemistry (2021). Link
A synthetic oscillatory network of transcriptional regulators, by Elowitz M.B. & Leibler S. Nature (2000). Link
Construction of a genetic toggle switch in Escherichia coli, by Gardner T.S. et al. Nature (2000). Link
Engineering stability in gene networks by autoregulation, by Becskei A. & Serrano L. Nature (2000). Link
Engineering Escherichia coli to see light, by Levskaya A. et al. Nature (2005). Link (Explained).
Genetic programs constructed from layered logic gates in single cells, by Moon T.S. et al. Nature (2012). Link
Programmable single-cell mammalian biocomputers, by Ausländer S. et al. Nature (2012). Link

Gene Drives

→Gene Drives on the Horizon, by the National Academies (2016). Link
Genetic Control of Mosquitoes, by Alphey L. Annual Review of Entomology (2014). Link
Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi, by Gantz V.M. et al. PNAS (2015). Link
Regulating gene drives, by Oye K.A. et al. Science (2014). Link
Current CRISPR gene drive systems are likely to be highly invasive in wild populations, by Noble C. et al. eLife (2018). Link

Engineered Microbial Communities

→Synthetic Biology Tools to Engineer Microbial Communities for Biotechnology, by McCarty N.S. & Ledesma-Amaro R. (2018). Link
Engineering microbial consortia: a new frontier in synthetic biology, by Brenner et al. (2008). Link
Emergent cooperation in microbial metabolism, by Wintermute E.H. & Silver P.A. Molecular Systems Biology (2010). Link
Syntrophic exchange in synthetic microbial communities, by Mee M.T. et al. (2014). Link

Metabolic Engineering

→Metabolic Engineering: Past and Future, by Woolston B.M. et al. Annual Review of Chemical and Biomolecular Engineering (2013). Link
Physiological limitations and opportunities in microbial metabolic engineering, by López et al. Nature Reviews Microbiology (2021). Link
Production of the antimalarial drug precursor artemisinic acid in engineered yeast, by Ro D-K. et al. Nature (2006). Link
Tuning genetic control through promoter engineering, by Alper H. et al. PNAS (2005). Link
Microbial production of fatty-acid-derived fuels and chemicals from plant biomass, by Steen E.J. et al. Nature (2010). Link
Complete biosynthesis of opioids in yeast, by Galanie S. et al. Science (2015). Link
Carbon-negative production of acetone and isopropanol by gas fermentation at industrial pilot scale, by Liew F.E. et al. Nature Biotechnology (2022). Link

Plant Engineering

→Plant synthetic biology, by Liu W. & Stewart Jr. C.N. Trends in Plant Science (2015). Link
Synthetic genetic circuits as a means of reprogramming plant roots, by Brophy J.A.N. et al. Science (2022). Link
Quantitative characterization of genetic parts and circuits for plant synthetic biology, by Schaumberg K.A. et al. Nature Methods (2016). Link

Recoded Genomes

→Reprogramming the genetic code, by de la Torre D. & Chin J.W. Nature Reviews Genetics (2020). Link
Synthetic Genome Recoding: New genetic codes for new features, by Kuo J. et al. Current Genetics (2017). Link
An expanded genetic code with a functional quadruplet codon, by Anderson J.C. et al. PNAS (2004). Link
Sense codon reassignment enables viral resistance and encoded polymer synthesis, by Robertson W.E. et al. Science (2021). Link
A swapped genetic code prevents viral infections and gene transfer, by Nyerges A. et al. Nature (2023). Link
Total synthesis of Escherichia coli with a recoded genome, by Fredens J. et al. Nature (2019). Link

Synthetic Cells

→Progress Toward Synthetic Cells, by Blain J.C. & Szostak J.W. Annual Review of Biochemistry (2014). Link
Towards a synthetic cell cycle, by Olivi L. et al. Nature Communications (2021). Link
Reconstitution of ribosome self-replication outside a living cell, by Kosaka Y. et al. bioRxiv (2022). Link
Transmembrane transport in inorganic colloidal cell-mimics, by Xu Z. et al. Nature (2021). Link
Programmable Fusion and Differentiation of Synthetic Minimal Cells, by Gaut N.J. et al. ACS Synthetic Biology (2022). Link

📙 Courses

* = Recommended

• What is Synthetic Biology? (EBRC)

• *Introduction to Bioengineering (Stanford)

• The Great Ideas of Biology (Caltech)

• How to Grow Almost Anything (MIT)

• Engineering Life: Synbio, Bioethics & Public Policy (Johns Hopkins)

• *Principles of Synthetic Biology (MIT)

• *Biological Circuit Design (Caltech)

• Cellular Design Principles (Purdue)

• Quantitative Microbiology (UCSD)

• Statistical Inference in the Biological Sciences (Caltech)

• Miscellaneous methods and lectures (CSBERG)

• *Physical Biology of the Cell (Caltech)

📚 Textbooks & Guides

(Recommended order. * = free.)

1. The Machinery of Life (a gentle introduction to the beauty of a cell.)

2. *Cell Biology by the Numbers (get a grasp for the numbers of biology.)

   1. See the accompanying YouTube course by Ron Milo.

   2. Use the Bionumbers database while doing your own calculations.

3. *Molecular Biology of the Cell

   1. Pay close attention to sections on the Central Dogma and metabolic pathways.

4. Synthetic Biology - A Primer (Revised Edition) and BioBuilder

5. *Underground Garden Club (get hands-on practice.)

6. *CRISPRpedia (online textbook about CRISPR.)

7. (optional) A Computer Scientist's Guide to Cell Biology

8. An Introduction to Systems Biology

9. Physical Biology of the Cell (a deep dive into biophysics.)

10. *Deep learning (see the accompanying computational biology course at MIT.)

📹 Video Channels

The Thought Emporium | Julia Bauman | Axial | The Sheekey Science Show | iBiology (Synthetic Biology series) | Foresight Institute | EBRC | Synthetic Biology One | Innovative Genomics Institute | Oral History of Agricultural Genetic Engineering

🔖 Books

• Genentech: The Beginnings of Biotech, by Sally Smith Hughes

• Invisible Frontiers: The Race to Synthesize a Human Gene, by Stephen S. Hall

• The Eighth Day of Creation, by Horace Freeland Judson

• Regenesis, by George Church & Ed Regis

• The Genesis Machine, by Amy Webb & Andrew Hessel

• The Gene: An Intimate History, by Siddhartha Mukherjee

• Life at the Speed of Light, by J. Craig Venter

• Higher Animals: Vaccines, Synthetic Biology, and the Future of Life, by Michael Specter

• What’s Your Bio Strategy?, by John Cumbers & Karl Schmieder

• A Crack in Creation, by Jennifer Doudna & Samuel Sternberg

• The Double Helix, by James Watson

• The Emergence of Life: From Chemical Origins to Synthetic Biology, by Pier Luigi Luisi

• Bio Design: Nature + Science + Creativity, by William Myers

• The Song of the Cell, by Siddhartha Mukherjee

• Synthetic: How Life Got Made, by Sophia Roosth

• The Singularity is Near, by Ray Kurzweil

✒️ Blogs & Original Essays

Codon (oh yeah) | Works in Progress | Asterisk Magazine | Decoding Bio | Asimov Blog | GROW Magazine | Biodecoded | The Century of Biology | Where Tech Meets Bio | Nucleate Signal | Sofia Sanchez | Sam Rodriques | In the Pipeline | Erika’s Newsletter | Biodraft_ | Positive Selection | Biocene Thoughts | Bowtied Biotech | Biomarker | The Glimpse | White Pill | Axial | a16z Blog | Future | Trevor Klee | Milky Eggs | Adaobi | Synthego Blog | Nintil | De Novo | Y Combinator | The Cell + Gene Curator | Twist Biosciences Blog | James Somers | Some Thoughts on a Mysterious Universe | Markov.bio

🎧 Podcasts

Grow Everything | SciBetter | Built with Biology | The Long Run with Luke Timmerman | Translation Podcast | The Readout Loud | The Bio Report | BioCentury This Week | Lady Scientist Podcast | Axial Podcast | Nature Podcast | Bio Eats World

🗞️ Journals

These are the journals that I check each week to find new papers. * = preferred.

*Nature Communications | PNAS | Current Biology | Synthetic Biology | Nucleic Acids Research | PLOS One (see the Synthetic Biology category) | PLOS Computational Biology | Nature Protocols | *Nature Biotechnology | Nature Chemical Biology | *Science | *Science Advances | ACS Synthetic Biology | *Nature | Journal of the Royal Society Interface | *Molecular Systems Biology | *Cell Chemical Biology | *Cell | EMBO Reports | eLife | FEMS Yeast Research | Scientific Reports | Nature Methods | *Molecular Cell | Metabolic Engineering | Nature Microbiology | PLOS Biology | Cell Reports | The New England Journal of Medicine | Current Opinion in Biotechnology | Current Opinion in Chemical Biology | Nature Chemistry | Nature Biomedical Engineering | Plant Biotechnology Journal | bioRxiv | Trends in Biotechnology | *Nature Journals (Synthetic Biology) | Nature Journals (Biotechnology) | Nature Journals (Computational Biology and Bioinformatics) | Nature Journals (Neuroscience) | Nature Methods | Bioinformatics | arXiv | Cell Systems | Nature Aging | Neuron | Nature Neuroscience | Science Translational Medicine | BMC Biotechnology | Communications Biology | Nature Metabolism | Journal of Industrial Microbiology and Biotechnology | GEN Biotechnology | Npj Systems Biology and Applications | Nature Cell Biology | Gene | PNAS | Nature Reviews Microbiology | Journal of the American Chemical Society | Molecular Therapy | *Nature Plants | Molecular Plant | Plant Cell | Nature Machine Intelligence

📰 News & PR Websites

* = recommended.

*STAT | *WIRED News | *Science | Ars Technica | *Nature Biotechnology | *SynBioBeta | Tech Crunch | PR Newswire (Synthetic Biology) | PR Newswire (Biotechnology) | Proto.Life | The Guardian | GEN Eng News | Labiotech | NY Times | Fierce Biotech | Nature News | The Scientist | New Scientist | MIT Technology Review | Washington Post | Quanta Magazine | Timmerman Report | Genome Web | BiopharmaDive | Endpoints News

🏘️ Communities

* = Broad, open membership.

iGEM | Engineering Biology Research Consortium | ValleyDAO | Build-A-Cell | *DNA Deviants | *Bits in Bio | SBOL Community | Biodesign Challenge

Thanks for reading. Please send suggestions for improvements to my email.

— Niko McCarty

I’ve been writing this blog for three years. What began as a weekly list of synthetic biology papers (here’s the first issue) has morphed into scattered essays, with many breaks along the way. This seems like a good time to reflect on what I’ve learned about writing words on the Internet (so far.)

My advice has little to do with the granular act of writing, like sentences or paragraphs. It is, rather, about all the external factors that influence how we write and what we choose to say. Every piece of advice is something I’ve struggled with personally. These are the things I wish I knew three years ago.

This essay isn’t about why you should write, either, because there are too many reasons to list: Writing is a way to manifest ideas. A well-written article will help you raise funds and build a team to make your ideas real. Writing will help you become a beacon. Conveying an idea simply will help you become a node through which opportunities flow. And writing is a way to think. It isn’t possible to craft a compelling essay without a relatively deep understanding of its ideas.

Now here’s my advice about how to write on the Internet.

Be consistent, but don’t stress over timelines.

If you want to write well, you first have to write badly. To write badly, you first have to care enough to begin. To begin, you should start a blog. Do it now. 

For every 100 people who say they want to write, perhaps ten will start a blog and publish something. If you do that, you’ve gone further than most. Start by writing short-form content on Twitter. Write about a paper you just read. Use writing as an excuse to explore an idea or business.

Publish regularly, but don’t stress over timelines. Writing is difficult enough without self-imposed deadlines. It’s better to post a great piece once a month than something bad every week. Devote part of your day to writing, and block off everything else during that time. Focused writing demands a maker’s schedule; not a manager’s schedule.

Be patient about growth. It took Scott Alexander eight years to become widely known. Ed Yong started a blog in 2006, published several articles each week for the next ten years, landed a job at The Atlantic in 2015, and won a Pulitzer in 2021. J.K. Rowling was rejected by twelve publishers for Harry Potter. J.R.R. Tolkien wrote The Lord of the Rings over a twelve year span and spent five more trying to get it published.

If you write what you love, success will follow. When Phil Sharp won a Nobel Prize in 1993, he said, “Never did I think I was going to necessarily see a Nobel Prize but I knew I was doing very good science and enjoyed that and that’s what life is about, it’s doing good science.” Ditto for writing.

Master story structures.

Learn how to tell a story. It is a formula, and the equations are written in books and on websites. Read advice on writing from other bloggers. Buy the book called On Writing Well, by William Zinsser. Read it at least once. Read Paul Graham’s essay about essays, and then read his other essay about it, too.

At the sentence level, use the active over the passive voice. “The castle was attacked” is passive. “Soldiers attacked the castle” is active, because a subject performs the verb.

Get rid of wasteful words and don’t repeat ideas, unless you’re really trying to emphasize a point. People don’t like to be told things twice. Support your ideas with examples. Specificity is the key to credibility.

Refine your story’s structure before fiddling with sentences. An apple pie tastes poor if sugar and apples are added to the butter too soon, and the order of events similarly matters in an essay. Map out your ideas before writing; a basic outline and story arc will help to de-vague-ify your idea and focus your words.

A topic is not a story. An essay about plastics in the ocean is impossible to write because there is no outcome; no way for the story to progress. Stories have angles and arguments. They have a punchline. And stories are not usually linear.

All essays should have a nut graph, a sentence or two that tells the reader what the piece is about, and why they should keep reading. It usually shows up in the second or third paragraph.

Consider Plenty of Room at the Bottom, the classic Feynman lecture. He begins by talking about great scientists who made a discovery that opened a new field. He then says, “I would like to describe a field in which little has been done, but in which an enormous amount can be done in principle.” And then comes the nut graph: “What I want to talk about is the problem of manipulating and controlling things on a small scale.” This simple sentence sets up the entire essay, and it appears near the top. Essays without a nut graph often feel rambly and unfocused.

It takes time to understand story structures. And beautiful writing comes with practice. It is easy to appreciate beauty when in front of us, but much harder to create it from a blank canvas.

Nobody cares, and that is good.

Most people learn to write in school. They write essays based on prompts given by teachers. Those teachers are then paid to read the essays and issue grades. But the real world does not work this way. Every piece of writing sinks or floats of its own accord. It floats if it has good ideas, limited jargon, and an interesting story. An article sinks if it’s boring or unclear.

If your writing sinks, there is no reason to be embarrassed. Nobody probably even saw it, and people have better things to think about anyway. Learn from it and move on. If your writing floats, great. Learn from that and move on, too.

Everybody has their own life, family, chores. Almost none of them are thinking about you. Embarrassment is self-inflicted. The same applies to “likes” on Twitter. Write what you want and tame the mammoth.

Be yourself.

Write like you talk. Not just at the sentence level, but also at the idea level.

Don’t write ‘utilized’ in a sentence if you wouldn’t say it to a friend. Blogs are meant to be entertaining. The goal is to get people to read your words, and everybody most enjoys reading informal, humorous writing.

At the idea level, write in a way that friends would recognize. Share drama and spill gossip. Richard Feynman and Freeman Dyson were both respected physicists who wrote blogs in simple terms, with lots of personal anecdotes. I think this is why their writing became popular.

George Saunders is a witty writer. But as a student at Syracuse University, he was trying to write “serious things,” and so his essays suffered. One Monday, Saunders went to a professor’s house for a writing workshop and the professor told every student to stand up and “tell a story from our lives, off the cuff.” Here’s Saunders:

“None of us wants to be a flop and so each of us rises to the occasion by telling a story…in something like our real voice, using the same assets (humor, understatement, overstatement, funny accents, whatever) that we actually use in our everyday lives to, for example, get out of trouble, or seduce someone. For me, a light goes on: we are supposed to be—are required to be—interesting…What we’re doing in writing is not all that different from what we’ve been doing all our lives, i.e., using our personalities as a way of coping with life. Writing is about charm, about finding and accessing and honing ones’ particular charms.”

Be interesting.

People read blogs that are interesting or useful. There is little time to read anything else. 

An idea is generally interesting if it can be conveyed in a short headline: “Biology is a burrito,” “Content is king,” “I should have loved biology.”

A good way to improve the amount of interesting in an essay is to multiply thrust and reduce drag. “The thrust of a piece is what motivates readers to invest the energy necessary to extract its meaning. It is the reason they click. Drag is everything that makes the reader’s task harder, such as meandering intros, convoluted sentences, abstruse locution and even little things like a missing Oxford comma,” writes Nathan Baschez. Remove boring sentences and extraneous ideas. Support your arguments with stories.

I recently read an entirely-too-long article about Wendell Berry, a writer who has renounced modernity and lives on a farm in Kansas. I couldn't care less about Mr. Berry or his farm, but I finished the article because it was well-written.

Similarly, readers do not care if you go “off-topic,” as long as the detour is interesting. My most popular piece is “A Brief History of Parafilm,” which has nothing to do with anything that I normally write about.

Metrics are overrated.

Audiences start small and grow fast. It took me five months to reach 1,000 subscribers, and the same amount of time to go from 2,000 to 5,000.

Don’t set arbitrary subscriber goals. Once you achieve them, you’ll move the goalposts and remain unsatisfied. Set specific goals instead: “I want to use writing to explore ideas for a company,” or “I want to blog to meet people with shared interests.”

A “small” audience is not limiting. Ash Trotman-Grant, a friend in San Francisco, wrote a blog about science video games and grew it to 250 readers. In May, he launched Karyo Studios with backing from a16z SPEEDRUN. Partners at the VC read his blog and now he’s building a sandbox game for synthetic biology. The blog fulfilled its purpose.

Social media is a false idol. Twitter and Reddit are finicky audiences, only a small fraction of whom will actually read your words. A post on Reddit with >1M impressions typically converts less than 1% of people into readers and <0.1% into subscribers. When my Substack was shared by a famous investor with 50,000 subscribers, I gained 23 subscribers. There are no good shortcuts to growth, other than good writing.

Virality is also difficult to predict. Low-effort posts often become unexpectedly popular. In general, follow BuzzFeed’s advice and “err on the side of publishing.”

Find your ilk.

Become friends with other writers. Send them your drafts, and edit their drafts. If you are kind, others will be kind to you. Send each essay that you write to at least three people.

Create a Junto. When Benjamin Franklin was 21 years old, he met with friends every Friday evening to debate “any point of Morals, Politics, or Natural Philosophy.” All members were expected to write an essay and read it to the group every three months. The goal was to provide “a structured form of mutual improvement.” Do this with your own friends. If you don’t know other writers, reach out to me and we’ll do it together.

Be explicit about your audience. “General audience” is not a real thing. You might as well light your words on fire and catapult them into a Black Hole. Hold one person in your mind, and write a letter to them. A defined audience makes it easier to tune the technical level of an essay and decide which jargon to keep or remove. Words to everyone will reach no one.

It often feels lonely to write online. Most readers will never contact you, even if you change their life. Sam Arbesman’s Overedge Catalog helped someone get a job, but he only heard about it much later.

When Sydney Brenner won the Nobel Prize in 2002, a Chinese researcher emailed him and asked, “Please tell me how to do it.” Brenner gave an answer during his acceptance speech in Sweden: “First you must choose the right place,” he said. And then, “choose excellent colleagues.” Ditto for writing.

Talk and read a lot.

The brain is a selective filter. It recalls interesting things and loses the rest. Ask good questions, and others will retrieve interesting details from their own life. It is quicker to find ideas by talking to others than to think up something on your own. A good idea is unique, easy to describe, and often shared in an excited voice. Cold email one new person every day. Follow up with them. 

Compelling ideas hide in plain sight. If you start to write regularly, you will find ideas everywhere, because you will naturally start to ask questions to uncover them. The more you think about writing, the more you’ll search for things to write about. Take notes after every conversation.

Read something wonderful every day. Reflect – really reflect – on the things you read. What resonated, and what fell flat? What would you have done better? Learn from the mistakes of others and avoid making them yourself.

Grab qualities from different writers and emulate them in your own writing. I strive for the voice of Richard Feynman, the empathy of Ed Yong, and the clarity of Grant Sanderson.

Find a reason; stick to it.

Writing is manifestation. It’s a way to raise money, build a team, or rally a community. But it takes a lot of time, and it’d be easiest not to do it at all. A clear mission will help you to push through failures. Joan Didion wrote to see the world. David Foster Wallace wrote to have fun. Freeman Dyson wrote to explain his ideas and connect with readers. 

Don’t try to please people. Just stick to your reason. Wallace, an American novelist, wrote: “At some point you find that 90% of the stuff you’re writing is motivated and informed by an overwhelming need to be liked.” Write what you want, and trust that readers will stick by you. 

It is okay to feel like your writing is flawed, a perpetual work-in-progress. It is okay to feel dissatisfied with the things you’ve written. It is okay to be unhappy.

But once you’ve found a reason, write. Then, write some more. From Annie Dillard’s Write Till You Drop: 

After Michelangelo died, someone found in his studio a piece of paper on which he had written a note to his apprentice, in the handwriting of his old age: ''Draw, Antonio, draw, Antonio, draw and do not waste time.''

Thanks to Tony Kulesa, Ash Trotman-Grant, and Claudia for reading drafts of this.

Note from our sponsor:

At Codon, we love tools that help biologists move faster. Primordium Labs will sequence your whole plasmids overnight for just $15, no primers needed. Faster, cheaper, and less hassle. What's not to like? Start sequencing.

1. My recent essay with Julian Englert is about a protein printer that could (theoretically) convert digital bits into physical atoms. Thank you to those who read it and left comments. Some highlights:

   • My friend Daniel Goodwin tells me that light-controlled proteins are remarkably slow to control. It could take many seconds to move the ribosome from one codon to the next, and so our hypothetical device might take hours to make a single protein.

   • Alex Reis asks if proteins produced with this method would fold properly. I’m not sure. Light-controlled protein synthesis is a sketchy technology, and a protein made slowly may not fold in the same way as a protein made quickly. A ribosome in a human cell adds five amino acids to a protein chain each second.

   • Max Berry left an excellent comment. I could write an entire article in response, but if you want to go deeper into this subject, I suggest you read it in full.

2. Gene-edited trees. For a recent study, researchers edited 21 different genes in poplar trees, a species commonly used to make paper. Separating cellulose from lignin — a key step in the paper-making process — emits about 150 million tons of greenhouse gases each year. By reducing the amount of lignin in wood, it is easier to get out the cellulose, and these emissions go down. The researchers studied trees with 70,000 different gene-editing combinations, just 0.5% of which had reduced lignin levels and extra cellulose. From an article in Science: “After 6 months, the most promising varieties had their lignin content reduced by 49.1% and their cellulose-to-lignin content increased by 228%. If a typical paper mill used these varieties, the team reports, it could increase its paper output by 40%, cut its greenhouse emissions by 20%, and boost its lifetime profits by about $1 billion.”

   

3. CNGA3-achromatopsia is a hereditary disease that causes people to see in shades of gray. Their cone cells, which are responsible for color vision, don’t work like normal. But what happens if you restore these cone cells, using gene therapy? Will they start to see in color, or will their brain be unable to handle the new sensation? This study injected a viral vector, carrying a healthy copy of the CNGA3 gene, into four people; three adults and one child. One eye was treated for each person, and the other left untreated. Each person said that their vision was different after the injection, but not in a dramatic way. They weren’t able to see slight differences between colors, such as blue versus green, but all of them could kinda see the color red. Two of them could also see yellow, and one person saw all three colors. Interestingly, when asked to describe the color red, “they often admitted that they had no appropriate words to describe it,” the study says. “When encouraged to find the exact wording, they said it glows differently, shines, or appears on a different plane than the background.”

   

4. There’s a TV show where a bunch of doctors are walking through a hospital corridor. They’re talking about a patient who has a rare genetic disease. They’ve just finished sequencing the patient’s genome, but they don’t have “DNA sorting” software. So, instead, they print out the patient’s entire genome and sift through it, by hand, to find the culprit gene. It’s hilarious, even if the premise isn’t too distant from how old-school geneticists used to operate. Unfortunately, the stack of paper shown in the TV show is about 30x shorter than the actual human genome. And that’s how I learned that there are published books that contain entire chromosome sequences.

Also, the Wellcome Collection in London has a complete, printed copy of the human genome. It fills up an entire bookcase!

7. I wrapped up my series on “30 Days of Great Biology Papers.” This was a series of tweets in which I told brief stories behind seminal papers, mostly in molecular biology and biophysics. You can read all of them here. A big takeaway from this exercise, for me, is that nothing is inherently obvious. I often wrote about papers that are extremely well-known, such as PCR and early papers from Francis Crick and Sydney Brenner. I assumed, falsely, that few people would care about these papers because they are already taught in school. But I was wrong. Those papers had the highest engagement.

8. A perennial dream of bioengineers is to make enzymes that break down plastic. It’s kinda like the holy grail of biology. Imagine if you could just dump all your plastic bottles in a dishwasher-looking machine at home, and enzymes inside then broke them down and recycled them. I wrote about one of these enzymes last year, when a group in Texas used machine learning to make a PET-degrading enzyme, called FAST-PETase, that could break down a pre-heated water bottle in about two weeks at 50ºC. That’s quite slow, unfortunately, and these enzymes also leave behind a mixed bag of chemicals. They don’t always break down PET into a form that is easily recycled. But for a recent paper out of Nanjing, China, researchers engineered another enzyme and showed that, when mixed with FAST-PETase, the two worked together to break down plastic twice as fast as the Texas enzyme alone. Together, the enzymes also produce much purer terephthalic acid, which can be recycled into new plastics.

9. A LEGO robot, made by undergraduate students at Arizona State University, pours sucrose gradients (a tube with dense liquid at the bottom, and less dense liquid at the top), which are used to separate, say, proteins from RNA by spinning them really fast in centrifuges. This robot joins a rich lineup of LEGO lab devices, including a microscope, liquid-handling robot, and cell printer.

   

10. The F.D.A. approved a gene therapy for hemophilia A for the first time. It’s called Roctavian and it’s only available for people who don’t have antibodies against AAV5, which is the viral vector used to deliver the gene therapy. The F.D.A. also approved a cellular therapy, called Lantidra, to treat a rare form of type 1 diabetes that affects roughly 3 out of 1,000 people with type 1 diabetes. The therapy works by replacing beta-cells with “fresh” cells taken from a, err…dead person.

11. Transcription factors are proteins that bind to DNA and control gene expression. At least, that’s what every textbook says. And it’s true, but only in an incomplete way. Because it turns out that at least half of them, in humans, also bind to RNA molecules. These protein:RNA duos seem to regulate gene expression in a way that we don’t really understand. And, at least in zebrafish, there are also lots of diseases that crop up when you mutate the bits of these proteins that bind to RNAs, including cancers and developmental disorders. I suspect this study will ignite a firestorm of research. Fortunately, there are many unanswered questions. How do transcription factors couple up with the correct RNA molecule? And how do they work together to control genes in the cell?

12. Winning a Nobel Prize reduces scientific output because the winner attends more events, talks to more journalists, and generally deals with more bureaucrats. From the Science article:

    Researchers behind the study analyzed data on Nobel Prize winners in physiology and medicine between 1950 and 2010, charting how three factors changed after their awards: the number of papers they published; the impact of those papers, based on how often they were cited; and how novel their ideas were…
    
    Before winning the prize, future Nobel laureates published more frequently than their colleagues who eventually won the Lasker Award, and they also published more-novel papers and garnered more citations. After winning a Nobel, however, the trend flipped: Nobel winners, on average, saw declines in productivity, novelty, and citations, dropping to even with the Lasker winners, or sometimes below them. In terms of raw numbers, future Nobel winners published about one study more per year than future Lasker winners in the 10 years leading up to the prize. In the 10 years after winning, however, the Lasker group published about one more study annually than did their Nobel laureate peers.

    Full study here.

    

13. In the 1930s, screwworm flies caused “180,000 livestock deaths in under half the counties in Texas,” according to a U.S.D.A. history. This fly, endemic to the Americas, feasts on decaying flesh. They lay eggs inside the wounds of dying cows. In response, the U.S. government funded a massive effort: To sterilize millions of screwworms, initially with hospital x-ray machines, and air drop them over Florida, Texas, and elsewhere. The irradiated males would compete with healthy males for mates, it was thought, and gradually cause the population to fall. A pilot experiment was conducted on an island 40 miles north of Venezuela. “In 1954, screwworm flies were mass reared in Orlando, Florida, by USDA scientists and flown to Curaçao, where 400 sterile males per square mile were released by air. Effective eradication was achieved in 10 weeks,” the report says. Later, the U.S. government reared and sterilized some 50 million screwworms per week and swiftly eradicated the insects in Florida and in the southwest.
    
    Now, I’m telling you this because using x-rays to sterilize insects is really inefficient. Some of the males leave the machines healthy-as-ever, and others become so unwell that they can’t seek out mates in the wild. A better option is to use CRISPR gene-editing, which is more precise and reliable. I’ve written about this before. But the basic gist is that you engineer female insects to express the Cas9 protein (one part of the CRISPR system), and engineer male insects to express guide RNAs. You then rear these insects together, in a massive warehouse. Their offspring have both the Cas9 protein and the guide RNA, which then cut two different genes: one for female survival and another for male fertility. When a gene-edited female lays her eggs, then, the female offspring never hatch, and the males hatch but can’t produce offspring of their own. (The male fertility gene is beta-tubulin, which helps sperm swim.)

    
    A company, Agragene, has now started greenhouse tests with this technology (it’s licensed from Synvect, a spin-out from Omar Akbari’s lab at the University of California, San Diego). They are rearing CRISPR-sterilized spotted wing flies, which eat strawberries and other fruits, and aim to release them into the wild to knock down pest populations and protect crops. This is much the same intellectual spirit that helped the U.S.D.A. obliterate screwworms in the 1950s.

    

14. Biotech company, eGenesis, is transplanting pig hearts into baby babboons. A spin-out from George Church’s lab at Harvard, the company has created pigs that carry about 70 edits in their genomes. Those edits eliminated proteins and viral genes that can cause immune reactions in people. The company plans to, one day, use organs from these gene-edited pigs to save babies born with congenital heart defects. For now, they are testing them in infant baboons — twelve in total. Two surgeries have been carried out so far, and “neither animal survived beyond a matter of days.” (Here is a good talk at the F.D.A. about how xenotransplants work and why they’d be so important. In 2019, about 4,000 Americans were waiting for a heart at any given time.) Meanwhile, David Bennett remains the only person to receive a pig heart transplant, and he died two months later from heart failure, not rejection. A recent study in Nature Medicine also did pig-to-human xenotransplants in two “brain-dead” people, monitored the organs for 66 hours, and saw no signs of “hyperacute rejection or zoonosis.”

    

15. Fractyl Health is making a “one-time gene therapy…to lower blood sugar and body weight using the same mechanism as semaglutide,” the weight loss drug. It’s ostensibly marketed for diabetes, but we all know where the real money’s at.

16. A complete, whole-brain connectome of the fruit fly has been published. All 130,000 neurons are annotated, along with 50 million connections between them. “For every neuron, one can now query its connectivity, size, neurotransmitter, labels, etc. but also analyze network graphs and find pathways between neurons,” writes Sven Dorkenwald, first-author of the study. The full connectome can be explored online. It’s even possible to digitally simulate the neural circuits that underlie eating or grooming, as a May preprint shows.

17. RNA export systems. Normally, RNA is confined to the cell in which it’s made. If we want to study RNA, or sequence it, then we need to kill the cells. No longer. A new paper from Michael Elowitz’s group at Caltech reports engineered RNA exporters that “efficiently and specifically package and secrete target RNA molecules from mammalian cells within protective nanoparticles.” This will open up many possibilities, including long-term studies of how transcription changes over time, in single cells, in response to cancer or a drug or anything else. These RNA exporters also work across many organisms and cell types, and they don’t interfere with gene expression or cell growth. This may prove to be the most important paper of the year.

    

18. A new method could build an entire E. coli genome — which has 3 million bases — in less than two months. The genomes are assembled from ‘megachunks’ of DNA, each stretching 500,000 bases, that are each put together in about 10 days. For context, it took two years for the same lab to synthesize and stitch together an E. coli genome just a few years ago.

19. Nearly all cellular compartments, in nature, are filled with liquid. Life is liquid. It is gooey, oozey stuff. And yet, the only rule in biology is that there are exceptions to every rule. A small number of microbes, we now know, also contain gas vesicles, which are hollow protein shells filled with air. These microbes use the empty vesicles for buoyancy; to float up-and-down in a lake, say, to maximize exposure to the sun for photosynthesis. In 2014, some clever engineers figured out how to express these gas vesicles in other types of cells and also showed that they produce contrast on ultrasound images. Gas vesicles can even be used to watch bacteria move through the body. And now, those same scientists have made miniature versions of these vesicles that measure just 60 nanometers across; roughly 1,700-times thinner than a piece of paper. These mini-gas vesicles still produce ultrasound contrast, but are now small enough to travel into tumors to deliver therapeutic payloads.

18. Eukaryotic cells (not humans!) naturally express RNA-guided endonucleases that, much like Cas9, use short snippets of RNA to ‘hunt down’ and cut DNA. These CRISPR systems, taken from various fungi and also from a mollusc, are widespread and can be reprogrammed to edit the human genome, all while carrying (perhaps!) a lower risk of immune responses. The proteins are called Fanzor, which is a cool name, and the paper is here.

19. Jiankui He, the CRISPR babies guy who spent three years in a Chinese prison and was released in April 2022, is back on the scene and tweeting about how he’s going to edit human embryos to protect them from Alzheimer’s disease. He does not immediately plan to implant the gene-edited embryos to cause a pregnancy, but reputable scientists, of course, have avoided engaging with the tweet like it’s the plague; just 133 likes after nearly 250,000 views.

20. A YouTuber, The Thought Emporium, is growing rat neurons in the laboratory. He says that, in a future video, he will use them to play the classic 1993 shooter game, DOOM. Are there other biology YouTubers that you enjoy watching?

21. Lots more CRISPR news, including dozens of new miniature gene-editing proteins. Two of these proteins are about 30% the size of Cas9, and thus much easier to package into viruses for gene therapy. Another paper recently reported an engineered Cas protein that is “up to 11.3-fold more potent than its parent protein…and one-third of the size of SpCas9.” And a third paper (BOOM!) reports Cas9 proteins that can penetrate into the central nervous system without being packaged into an adeno-associated virus, all while causing a lower immune response than a prior version of the same technology.

22. A great resource on biosecurity, written by Aron Lajko. There are many reasons why you should read Aron’s work, and then work on this problem. Here are just a few:

    • About 30,000 people know how to synthesize an influenza virus, at a cost of about $5,000.

    • The standards for screening possibly pathogenic DNA sequences are, to put it bluntly, a joke. Every DNA synthesis company basically does their own thing. “No US or international law requires companies that print DNA sequences to check what exactly they’re selling or who they're selling it to,” writes Kelsey Piper in Vox. Benchtop DNA synthesis machines will likely make it easier to create pathogens.

    • AI tools may not make it easier for someone with existing knowledge to create a pathogen, but they will lower barriers to entry.

    Recent talk by Kevin Esvelt for the Foresight Institute.

23. “How to clone a plasmid really fast and have it work basically every time.” A blog by Olek Pisera, PhD student at UC Irvine. More scientists should write stuff like this. Let me know if it works for you!

24. milky eggs on lifespan extension. A long, speculative review of the evidence. Main takeaways: Rapamycin is possibly OK. Lots of fiber is good. Eat a healthy diet and avoid simple sugars. Exercise a lot. Use sunscreen.

25. A new method can mutate up to 15,000 bases of DNA in bacterial cells at rates 6,700-fold higher than normal. This is, in other words, an "evolution supercharger.” The tool was crafted with a virus, called GIL16. The authors took the genome from this virus and replaced its “bad” genes with a gene to be mutated. GIL16 also encodes a DNA polymerase that specifically recognizes, and replicates, only these genes. An AI tool, AlphaFold2, was used to make the viral DNA polymerase dramatically more error-prone. Now, when they put the viral DNA, along with the gene of interest, into a bacterium, the cells rapidly mutate just the added DNA, while leaving the normal genome alone. In about two weeks of work, the researchers evolved cells that can eat methanol 7.4-fold faster than normal. This isn’t the first tool to super-charge evolution, but it is the first to do it in bacteria.

26. Tony Kulesa wrote a blog about Y Combinator and why it has been uniquely successful. It’s a really great piece with lots of insights. Can we emulate this model for high-capital industries, like biotechnology? Or for creative pursuits, such as writing?

    Beginnings

    A relatively small amount of force applied at just the right place

    If you enjoyed this, subscribe below. You might like this review of Tyler Cowen and Emergent Ventures for more on this topic. There are thousands of smart people who could start companies and don't, and with a relatively small amount of force applied at just the right place, we can spring on the world a stream of new startups that might otherwise not hav…

    Read more

    3 years ago · 18 likes · Tony Kulesa

27. A minimal cell, with just 473 genes, evolves just as fast as a cell with a normal-sized genome. In other words, evolution is not dependent on ‘throw-away’ genes. It persists at much the same rate, even when every gene is considered essential for survival. This claim comes from a new study in Nature. A few years ago, scientists made a “minimal” version of Mycoplasma mycoides, a parasite that infects goats and pigs. They eliminated hundreds of genes from this organism, which already had the smallest genome of any species that can be independently grown in a laboratory. This minimal cell, first reported in 2016, was about half as fit as a normal M. mycoides cell. They grow slowly and generally look sluggish. But now, this new paper shows that the minimal cells have regained normal fitness levels after 2,000 generations. Each nucleotide in the cells’ genome was hit with a mutation about 250 times during those 2,000 generations. That’s quite a lot. The evolved, minimal cells also swelled about 85% in diameter, which corresponds to a tenfold increase in volume. As the surface area-to-volume ratio shrinks, cells are able to do more stuff for less energy. But a bigger size also means that biochemical reactions become more limited by diffusion. This is a trade-off, of course; a bigger size is generally good when you have ready access to nutrients, such as in a laboratory.

28. Memes.

    

    

This essay is a thought experiment about a protein printer, a new technology to convert digital bits into physical molecules. It is speculative writing, because this printer doesn’t yet exist. But there are no physical reasons that it couldn’t, and we think it could change biology as much as printers changed the news.

We are living through an inflection point in biology’s history, in which a simple laptop can design proteins with wondrous new functions. Scientists at the Institute for Protein Design have crafted proteins that self-assemble into nanomaterials or that can be used as vaccines for the flu and HIV. In the future, “designer” proteins could be used to make new medicines or clean up toxic spills in the environment.

But “progress in science depends on new techniques, new discoveries and new ideas, probably in that order,” said Nobel Laureate, Sydney Brenner. And, unfortunately, it’s much simpler to design a protein than to build one. Computers are plentiful and electricity is cheap. Millions of proteins can be sculpted in the digital world, but each one costs at least $50 to make in the real world. That’s because proteins are made, in the laboratory, using synthetic DNA and cells; and DNA is expensive. Hundreds of protein designs must also be tested before we find one, finally, that works. 

Our machine would make proteins without using any DNA or cells. It could be sold as a kit, and could theoretically make one billion unique proteins for about one dollar.

Much of the following text is speculative. We’ve tried to point out intellectual holes, but we hope you’ll reach out and leave comments. This isn’t a grant proposal; it’s just us speculating about how to solve a problem, much like we would at the bar on a Friday night. After all, that’s the place where many scientific ideas first take form and begin their slow journey toward reality.

Note from our sponsor

Fifty Years supports early-stage founders solving the world’s biggest problems. Their Fifty 50 program teaches entrepreneurial PhDs/postdocs in Bio or Climate everything they need to start a company. If you know someone who could be a fit, nominate them.

II. Polymers

A protein is a long rope, speckled with beads, and each bead is an amino acid with a distinct shape and charge. The order of beads determines the final form of a protein; sequence begets function.

Proteins act as machines and messengers inside crowded cells. Some catalyze reactions 30 million times per second. Others break down food and build up cell walls, or capture carbon and store it in sugar molecules.

All cells make proteins in two steps: DNA is transcribed into messenger RNA, which is then translated into protein. This is the Central Dogma, a concept taught in textbooks and whispered about by biologists in reverent undertones. It is the untouchable foundation of molecular biology. But we will try to convince you that, perhaps, we can do better.

The ribosome is a molecular printer that threads ‘beads’ onto a protein string. It moves along RNA and reads three letters at a time, called codons, to build the amino acid sequence of a protein. The codon ‘GCA’ encodes alanine, ‘CUC’ encodes leucine, and so on.

Now, when we try to make proteins in the laboratory, there are only two options: Build with chemistry or harness the ribosome. The first option takes individual amino acids and fuses them together to form a chain. Chemists can make proteins with up to 164 amino acids in a few hours, but this requires specialized equipment and chemicals.

The second option, which is more common, is to design a protein on a computer, work backward to turn its amino acids into a DNA sequence, and then send that out to a chemical synthesis company. Scientists build the physical molecules and return them in the mail. The gene is then inserted into cells, and the ribosome does its thing and makes the protein.

But this is too many steps. It’s like writing before printers were invented. It’s like sending a text to a printing house, only to see your work weeks or months later. What we need, really, is a printer that takes words from a screen and quickly converts them into a physical book. In other words, we need to hijack the ribosome to turn bits into molecules, without DNA.

A typical protein has 400 amino acids, and each amino acid is encoded by three letters. This means that 1,200 bases of DNA must be ordered to build one average protein. Most DNA synthesis companies, such as Twist Biosciences, sell genes for as little as 7 cents per base, so a gene usually costs between $50 and $300. Many companies are building new technologies to make longer pieces of DNA, but we’re not aware of any that intend to cut costs. 

Hence, our search for a cheaper and faster way to make proteins.

When we envision what a protein printer might look like, we think of a sort of rotary telephone in which all the different codons — AUA, AUG, AUC, and so on — are placed on a single, continuous loop of RNA. The ribosome would then be engineered to ‘hop’ from one codon to the next to build custom proteins.

This would require that we reimagine core parts of the Central Dogma, which won’t be easy. But we’ve workshopped the idea with ribosome engineers, and not a single person said, “This is impossible” or “This breaks a law of physics.” Two people sent emails with sketches of how this protein printer might work, and one said that his research group had thought about pursuing a similar idea.

So, here’s the plan…

III. Blueprints

The first step is to build a loop of RNA that encodes all the different codons. This is simple. We’ll start by making a linear RNA strand, using chemistry or biology, and then fuse the two ends together with a ligase enzyme. Circular RNAs are translated by the ribosome, just like normal RNA, but decay far more slowly because they are not easily recognized by “degrader” enzymes. Circular RNA has a half-life of 24 hours or longer, compared to perhaps a few minutes for linear RNA. 

The circular loop does not have to contain all 64 possible codons, because the genetic code is redundant and there are only 20 amino acids. But the loop should have a diameter wide enough for the ribosome to freely move around.

Now, the next steps are more difficult to solve, because they require ribosome engineering.

Ribosomes are made from dozens of smaller proteins and RNA strands that come together in a brilliant symphony of molecular finesse. This machine evolved over billions of years to be incredibly precise, and to move along an RNA strand by one codon at a time. And we want to subvert this.

For simplicity, we'll focus on the bacterial ribosome, which is made of two subunits, called 50S (large) and 30S (small), that are held together with non-covalent bonds. Amino acids are carried into the ribosome on tRNAs, which enter the ribosome on one side and exit out the other. This happens about ten times every second. Fresh proteins emerge from the ribosome like beads threaded on a string.

Now, for our machine to work, we have to carefully track the position of the ribosome as it moves along the loop. The ribosome should move to a specific codon, and then some kind of signal, perhaps a molecule or light, will signal, “Hey, add an amino acid at this position!” None of this will work if the ribosome falls off and we lose track of its position.

In a normal situation, inside cells, ribosomes grab onto short RNA sequences, called ribosome binding sites, to initiate translation. We’ll place one of these binding sites in the loop next to an ‘AUG’ start codon. The ribosome will grab onto this sequence, move to the start codon, and then will stay there, stuck, until we add tRNAs to its environment. 

We’ll also tether the small and large subunits together — which has been done before — to keep the two ribosome halves together. A small protein “latch” would then clasp the ribosome together and keep it from falling off the RNA loop.

So now we have a ribosome that is stuck at the start codon on the RNA loop. How do we make sure that, as it moves along the circle, it only adds amino acids at the codons we specify?

This may be possible with a “protein gate” that physically blocks tRNAs from entering the large subunit. The protein gate could be clicked ‘on’ or ‘off’ using light. This sounds a bit like science fiction, but similar light-sensitive protein switches have been made in the past. It may be challenging, though, to make sure that only one amino acid is added each time.

Now, for the final part of our protein-making machine, we need to figure out how to make the ribosome “hop” or “slide” from one codon to the next. And this is no small feat.

“The ribosome is so engineered, so evolved, to not move in anything other than the three codon units,” says Jessica Willi, a biological engineer in Michael Jewett’s laboratory. “You may have to rebuild the entire small subunit to make this happen.”

*Gulp* Still, we think there are a few options to make this work.

Our first idea was to fuse the ribosome to a protein motor that burns chemicals to do physical work. Several DEAD-box proteins bind to RNA, and perhaps they could be fused to ribosomes to pull them along the RNA loop.

Another option is to hijack ribosome “sliding.” Sometimes, in nature, ribosomes get stuck on RNA or they have to skip certain codons. Excellent work from the Max Planck Institute shows that these ribosomes will stumble along an RNA strand — without adding amino acids to a protein! — until landing at a specific RNA sequence, where they resume translation. 

Sliding starts when a “loop” in the RNA pushes the ribosome into a hyper-rotated state. A protein called EF-G then “fires” and burns energy to push the ribosome along. Perhaps we could hyper-rotate the ribosome artificially, using light (at a different wavelength than the protein gate) or another signal to coax the ribosome into this “gliding” state.

Each codon in the RNA loop would be placed next to a sequence that stops the ribosome from gliding, or surrounded by a hairpin structure that physically blocks the ribosome from moving further. 

When the ribosome stops at each codon, a blue light signal would trigger it to add an amino acid, whereas a red light signal would push the ribosome onto the next codon without adding an amino acid.

None of these options are perfect, of course. We are fighting billions of years of evolution. The small subunit is exquisitely sensitive; it acts as a sort of brake pedal to stop the ribosome from slipping, says Alan Costello, a ribosome engineer, and so we’d have to loosen the small subunit’s tight grip on the RNA. 

The tolerance for errors in this protein printer is also low. A typical ribosome makes a mistake once for every ten thousand amino acids. There has been a lot of recent progress in ribosome engineering, but we’re likely still years away from designing such an intricate, molecular machine with anything matching natural levels of precision.

But, fortunately, it doesn’t have to work perfectly straight away. Methods improve, slowly, over decades (just see the story of PCR, which was awful in the beginning). This protein printer could be tested, initially, by coaxing it to make small proteins with just a few amino acids. There is a tiny protein, with just 12 amino acids, that emits a fluorescent signal (manuscript in preparation). That means we could make many variants of the protein machine, put each of them into a different tube, program them to make this tiny protein, and see which tubes give off the most fluorescent signal.

IV. Plans

This essay is speculative. But by pondering theoretical solutions to a problem, we often think more deeply about the nature of the problem itself. 

Remember that protein design has three steps: Design the protein, build it, and make sure it works. The first problem will likely be perfected in the near future, using some fancy AI models. This essay deals with the second problem, but it does not touch on the third. Protein design will only reach its full potential when the second and third problems get solved.

Adaptyv Bio, the company that Julian (a co-author of this essay) co-founded, is trying to solve the third part. They are building a foundry, where scientists can submit protein designs via an API and have them tested on automated workcells. By miniaturizing protein synthesis and characterization, and removing manual steps from the process, they aim to bring down the cost of protein engineering and help more people design proteins.

Still, the major obstacle in testing more proteins is the cost of DNA. So let’s see how our method compares.

A living cell burns 2 ATP and 2 GTP for each amino acid added to a protein. It costs about $1 for one milligram of GTP and about $1 per gram of ATP (a negligible cost). One gram of amino acids costs about one penny.

Let’s assume that our device requires 1,000 molecules of GTP and ATP to make an average protein. One could theoretically make 1 x 10¹⁸ proteins, then, for a thousand dollars. Even if you make a million copies of each protein, two trillion different kinds could be made for the same amount of money.

If the protein printer can be controlled with light, then its uses become even more profound. In the future, we may be able to design a protein on a computer, use a Python script to convert its amino acid sequence into a series of flashing lights, and then use those lights to move ribosomes to make proteins in real-time.

A student could even use LEDs, attached to an Arduino board, to control protein synthesis in a little tube. Or, a matrix of 64 x 64 LEDs, which costs about $50, could program protein synthesis in 4,096 wells at once. Light-based manufacturing is an established field, and more complex technologies are already used to make computer chips and 3D-printed parts.

But who is going to fund all of this? Maybe Speculative Technologies or Schmidt Futures have the money and desire. Or, perhaps, you are reading this and know how to make it all work — a solution has floated into your mind — and you’re buzzing to get started. We hope that’s true, because it would validate the entire notion that speculative writing can still drive progress forward.

So what are you waiting for? Let’s give it a shot.

Julian Englert is the CEO of Adaptyv Bio. Check out their blog to learn more about what the team is building to make protein engineering easier.

Cite as: McCarty, N. & Englert, J. A Protein-Making Machine. 2023 July. Available from https://www.readcodon.com/p/machine 

Thanks to Erika DeBenedictis, Alan Costello, Michael Jewett, Devon Stork, Camila Kofman, and Jessica A. Willi.

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

1 of 30. Y’know that feeling when you look at a “To Do” list, and you see all the words and scribbles on it, and just think, “Where do I even start?” Yeah, that feeling. It’s overwhelming. And it’s been my life for the last few weeks. I’m writing long essays for Asimov every other week and my work at MIT, where I’m helping to design a genetic engineering curriculum for undergraduates, has reached its crescendo. I’ll post an update soon.

Since the last Codon Digest, I’ve published:

• Reasons to Be Grateful for Biotechnology (with Avadhoot Jadhav)

• AAV Foundations (Part I)

  • An overview of AAV-based gene therapies, how they get made, and where they go wrong.

• AI-Designed Promoters (Part II)

  • How Asimov is using transformer models to design promoters that are only active in specific tissues, like the heart.

2 of 30. In early June, I was asked to sponsor a prize for the Bio x ML Hackathon. I offered to write about teams that make “a useful tool for wet-lab scientists.” To my surprise, the organizers agreed. Short write-ups on my three winners are scattered throughout this newsletter.

Codon Prize Winner #1: SynXNA

A project by Jaymin Patel at UC Berkeley and Pol Arranz-Gibert, formerly at Yale.

Anyone who has tried to engineer a cell knows how tedious it can be. DNA sequences are designed on a computer, and it takes a dozen or more clicks to change a single nucleotide. DNA sequences are also checked by hand, so it’s easy to make a mistake. Erika DeBenedictis, a group leader at the Crick Institute, writes:

I happened to need to test out 60 different specific point mutations of a protein I was working with…

To do so, I faced the prospect of clicking and typing 60 times to make 60 different plasmid maps on Benchling, clicking a whole bunch to design each of 60 sets of primers, then using my hands to clone 60 plasmids (a lot of pipetting)…

The indignity!

Lab robots are relatively inexpensive and can speed up the pipetting bits. But the computational design of a living cell is still slow and non-automated. SynXNA wants to change that.

The model takes a query (such as “make aspirin in E. coli”) and works backward, one step at a time, to build out a biosynthetic pathway. It first finds the enzyme needed to convert a metabolite into aspirin. Then, it finds an enzyme that can turn that metabolite into another metabolite. And it repeats this, again and again, until it wends its way back to glucose. The tool outputs a DNA sequence that encodes all the required enzymes.

“In the short term, the dream would be to output not just the plasmid,” Patel says, “but for the [the tool] to say, here are the five parts you need to order right now.” That would be nice, but the tool doesn’t work every time.

SynXNA integrates a GPT model from OpenAI with NCBI, BRENDA, and Wikipedia. The databases work together to restrict the range of acceptable outputs and cut down on hallucinations. This approach is similar, in many ways, to a convolutional neural network that was recently reported in the journal Metabolic Engineering.

A live demo is available online, but “it chews through OpenAI credits,” Patel says. “Every query is like $2.” So take it easy!

3 of 30. Cells are very fast and crowded places. A typical enzyme collides with its substrate 500,000 times per second. A molecule of glucose travels at 250 miles per hour. A protein rotates at 60 million RPM.

Let’s be real. These numbers sound made up. I pulled them from a 2011 blog post (oH mY goD tHat’S nOt pEEr-ReVieWeD!!!) by a computer scientist, named Ken Shirriff. I didn’t believe some of the numbers, so I emailed Ken and asked him: “Where did they come from?”

He graciously supplied receipts.

The speed at which glucose travels is governed by the equation v = sqrt(kT/mass). The mass of a glucose molecule is 2.99 x 10^-22 grams, so this equation comes out to 118 meters/second or 264 miles per hour. This is discussed on page 4 of the Cell Movements textbook.

The protein tumbling speed (which sounds like the most ludicrous number of all) is discussed in this article, which says that a typical rotational correlation time is about 8 nanoseconds. That’s the time it takes a protein to rotate 1 radian. There are 2π radians in a circle, so this works out to 1 billion rotations per second. Just note that the protein isn’t spinning in a perfect circle, like a figure skater, in clean and continuous rotations. It is, rather, twisting back-and-forth at a blistering pace, in every possible direction. Some proteins also have much longer rotational correlation times; closer to 20 nanoseconds.

And, finally, there is the collision question. Shirriff pointed to a website that says acetylcholinesterase, an enzyme, catalyzes 30 million reactions per second. If we assume that each molecule must collide with the enzyme before it is converted into something else, then the true number of possible collisions between an enzyme and substrate is far higher than 500,000 molecules per second. But my question was not about catalytic turnover. It was, “How do we know how many molecules physically collide with a protein in a given unit of time?” And this is more difficult to answer.

David Savage, a biophysicist at UC Berkeley, helped me figure it out. (Thank you!) He pointed to an article by my former PhD supervisor at Caltech, Rob Phillips (embarrassing), that describes how to use Fick’s Law (see figure 3 here) to estimate the number of molecules that collide with an object based on diffusion coefficients and molecular concentrations.

I’m working on a piece that explains these ideas, and how they can be experimentally measured. Stay tuned.

4 of 30. The Homebrew Biology Club is hosting an open contest. The top prize is $10,000.

To enter (it’s free), create an open lab notebook, work on a biology project this summer, and document your progress. Join the Discord server, too. Sebastian Cocioba, Manuel Montori and I will choose finalists in early December. Email me if you’d like feedback on an idea!

5 of 30. An anti-aging talk by Juan Carlos Izpisua Belmonte, a biochemist at Altos Labs, was so crowded and overfilled with people that police showed up and ejected half of them. In 2016, Belmonte “reported that sick mice lived 30% longer than expected after receiving a cocktail of special reprogramming proteins,” according to the article in MIT Technology Review.

6 of 30. Machine learning papers worth your time:

• A computational method to design large, self-assembling protein nanomaterials. It’s quite impressive. The scientists made protein assemblies with icosahedral symmetry containing 240, 540, and 960 subunits. The final protein assemblies measured 49, 71, and 96 nm in diameter, making them the largest computationally-designed protein assemblies so far.

• Bayesian optimization, a method used to fine-tune neural networks, was applied to genetic circuits. It “outperforms other optimizers by a substantial margin,” according to the study, and was used to optimize the fatty acid biosynthesis pathway in E. coli.

• My favorite: A large language model takes instructions, in English, and then automatically programs a robot to synthesize a molecule. It was used to make catalysts, a dye, and an insect repellant. All the code is available online. This reminds me of the Chemputer, “an autonomous compiler and robotic laboratory platform to synthesize organic compounds on the basis of standardized methods descriptions,” that was reported back in 2019.

7 of 30. Codon Prize Winner #2: Sequence Diffusion

A project by Jacob Gershon and Sidney Lisanza at the Institute for Protein Design.

Sequence Diffusion is a tool to create proteins that don’t naturally exist in nature. It creates both protein structures and sequences.

At first, I didn’t understand why this tool was different, or better, than the dozen-plus other AI tools to design proteins that already exist. But the keyword here is simultaneously; the tool makes it easier to see the relationship between a sequence and a structure, which will help students learn protein design.

“The sequence is what you'll order and express in an organism at the end of the day, while the structure helps verify that the protein does what you want," Gershon says. And "modeling both guarantees better structure-sequence convergence."

There’s a live demo available online. It’s a bit easier to use than other protein design tools that I’ve seen. The tool can be used to make a protein more soluble, change its charge, make it more stable at high temperatures, or completely redesign the scaffold around an active site.

In a preprint from May, David Baker’s team used this tool to hide a therapeutic peptide inside of a protective protein shell. The peptide is released only after the shell gets cleaved by an enzyme. From the study (emphasis added):

We chose to scaffold the pore-forming peptide melittin currently being explored as a cancer therapy. Starting with the melittin sequence and a flanking cleavage site, we generated an additional 125 residues to scaffold the peptide into a globular protein. Melittin-scaffolded proteins generated by the model were in agreement with AlphaFold2 models…We obtained synthetic genes encoding 12 proteins scaffolding melittin and found that 9/12…had the correct secondary structure.

The web tool takes 1-2 minutes to run. “Right now, it can only make one protein at a time,” Gershon says, simply because the demo has limited compute resources. “To make good [protein] candidates, you probably want to generate a thousand at a time.”

8 of 30. A phage is a virus that infects bacteria. They have been used to treat infections for more than 100 years. And now they’re making a comeback in the United States.

A French-Canadian microbiologist, named Felix d’Herelle, discovered bacteriophages in 1917 and used them to treat bacterial infections. The Soviet Union copied his example and used phage to treat “everything from typhoid fever to cholera.” A blog post for the American Society for Microbiology:

Early studies were promising, though experiments were often improperly designed by today's standards (i.e., lacked placebos or control groups, among other issues). The results were also published in non-English journals, making them largely inaccessible to Western scientists. Nevertheless, phage therapy did have a stint in the U.S. Throughout the 1940s, several U.S. pharmaceutical companies produced phage preparations to treat various infections…

However, phage therapy eventually fell out of favor in the West…After World War II, phage therapy research and use continued in eastern European countries, where it persists to this day…phage therapy is still a routine medical practice in Georgia, Poland and Russia.

However, the war prompted scientists in western Europe and the U.S. to avoid phage therapy, given its close ties to the former Soviet Union. The discovery of penicillin was the final nail in phage therapy's coffin—the advent of antibiotics revolutionized how bacterial infections were treated and became the gold standard in much of the world.

Now, with antibiotic resistance on the rise (for some, but not all, bacteria), phage therapies are moving back into the mainstream. Last year, phage therapy saved an Algerian toddler’s life. A paper published in May also uncovered eight different phages that can selectively kill off E. coli in mice.

The company behind the latter work, SNIPR BIOME, also recently announced results from a phase I clinical trial. They used phages, armed with CRISPR payloads, to selectively kill E. coli in the GI tracts of 36 healthy adults.

And for another study, researchers engineered bacteriophage T4 to target and deliver payloads to human cells, simply by swapping around the proteins on their outer shells and then coating them in positively-charged lipid molecules. A T4 phage can hold 171,000 bases of DNA or other molecules, including proteins and RNA. They’re incredibly versatile. (For context, the AAV9 that is often used in gene therapies has a packaging limit of 4,700 DNA bases.)

9 of 30. Three recent plant papers.

The first presents a new method to count mRNAs and proteins, in individual plant cells, at the same time. It uses single-molecule RNA fluorescence to measure mRNAs and fluorescent reporters to measure the proteins. It looks like it’ll be useful to track transcriptional and translational changes in plants as they develop.

The second paper is about PHYTOMap, a new technique to measure 3D spatial gene expression in plant tissues. In other words, it can measure which mRNAs are switched “on” or “off” in plant cells in both time and space.

The third paper is my favorite. By editing a single gene involved in phospholipid biosynthesis, called RBL1, researchers made rice plants resistant to multiple pathogens, while maintaining normal yields. Pamela Ronald, the plant geneticist at U.C. Davis who helped create flood-resistant rice, wrote a great Twitter thread about the paper. Recommend.

10 of 30. Focused ultrasound uses high-frequency sound waves to target tissues deep in the body. It is both safe and non-invasive. But the sound waves can’t pass through an adult human skull.

A Caltech group, led by Mikhail Shapiro, inserted a piece of strong, transparent plastic into the skull of a man undergoing reconstruction surgery. They were then able to shoot sound waves through this window and monitor neural activity across the whole brain. It’s the first time focused ultrasound has been used for high-resolution (200 microns), large-scale brain imaging (50 mm by 38 mm) in a person. As the man played a video game, or strummed a guitar, the neural patterns underlying his finger movements were decoded with 84.7% accuracy.

(A different preprint also reported that focused ultrasound can also be used to control genome and epigenome-editing tools in live animals. In other words, sound waves were used to switch CRISPR tools “on” and “off.”)

11 of 30. Biology operates on extreme scales. From a prior Codon blog:

The smallest living thing is Nanoarchaeum equitans, an ocean-dwelling cell that was first spotted in a hydrothermal vent off Iceland’s coast. It measures 0.4 micrometers across, about 125 times smaller than the thickness of a sheet of paper. The world’s largest organism is a seaweed clone, called Poseidon’s ribbon weed, which is 4,500 years old and stretches across Australia’s Shark Bay.

The scales of individual lifeforms are well known. But how often do we think about the scales that exist within a cell? Protein sizes span several orders of magnitude. Titin, the largest protein, has more than 30,000 amino acids. LIL, perhaps the smallest protein with a biological function, has just 26. Placing LIL next to titin, I imagine, would look a bit like placing a pea next to a volleyball.

Or, consider the ludicrous number of permutations that biological sequences can adopt. The human body contains at least 10¹² different antibodies, for example, and a DNA sequence with 100 nucleotides (which is quite small) can take 4¹⁰⁰ permutations, which is many orders of magnitude greater than the number of atoms in the universe. It is impossible to test even a tiny fraction of DNA and protein sequences.

12 of 30. The United States Department of Agriculture (USDA) “has authorized the sale of cell-cultivated chicken—chicken grown from stem cells in a bioreactor—from two Bay Area-based food technology companies, Good Meat and Upside Foods,” according to reporting in TIME and elsewhere.

The U.S. is the second country to green-light cultivated meat, after Singapore. Rollouts will begin in “high-end restaurants.” Upside Foods is apparently sending a batch of cultivated chicken to Dominique Crenn’s restaurant in San Francisco.

An Israeli startup, Steakholder Foods, also recently made the first 3D-printed fish filets. They use a 3D printer, loaded with animal cells, to physically print the fish. The whole thing only takes a few minutes.

A U.K.-based startup, called Uncommon, also raised $30M. They are using mRNA to “coax” cells into forming tissues without actually changing their DNA. It’s basically a ploy to sidestep regulatory challenges.

Investor confidence in alternative proteins remains high, even though it’s difficult to scale cultivated meat and slash prices further. This essay, in Asterisk Magazine, is the best I’ve seen at explaining why cultivated meat is so expensive in the first place. (One reason is that amino acids, the building block of proteins, cost an estimated $7 to $8 per pound of cultivated meat. This is just an estimate. Growing cells at massive scales, without contaminating them, is also a big challenge.)

13 of 30. One pound of decaffeinated coffee costs $0.50-$1.00 more than regular beans because it is expensive to remove caffeine during the roasting process. Now, companies and research institutes are trying to make coffee trees that are naturally caffeine-free.

A German, Ludwig Roselius, was the first to patent a method for decaffeinating coffee, in 1906. It involved heating raw coffee beans in salt water and then flooding the beans with benzol, a carcinogen. Fortunately, we soon found better ways to strip out caffeine.

Today, at least four methods are used. Two of them use safe(r) solvents, methylene chloride or ethyl acetate. Another option is to use the Swiss Water Process (which is the most expensive and is offered by a single company), which uses little more than water and heat to decaffeinate coffee beans. Most coffee makers still use chemical removal methods because they are cheaper. And they don’t need to be disclosed on a label.

The Guardian recently reported that a Brazilian coffee research institute will — over the next two decades — breed arabica coffee trees "that are naturally decaffeinated." The goal is to selectively breed plants that lack caffeine biosynthesis genes. Tropic Biosciences, a UK-based company that I previously wrote about in my Gene-Edited Bananas piece, is trying to do the same thing, but not in two decades…in the next couple of years.

We know the genes involved in caffeine biosynthesis because several coffee varieties are naturally caffeine-free. Coffea humblotiana, a tree native to the Comoro Islands located about 300 kilometers off the eastern coast of Africa, does not produce caffeine. Robusta beans have about twice as much caffeine as Arabica beans. Several studies have used CRISPR gene-editing to knock out parts of the caffeine biosynthesis pathway. Maybe we’ll get tastier decaf coffee.

14 of 30. So much cell and gene therapy news. I’m not sure where to start. Bullet points feel appropriate.

• The F.D.A. approved Sarepta’s one-time gene therapy for Duchenne muscular dystrophy, but limited its use to younger patients. It will cost $3.2 million. In May, an advisory panel narrowly recommended approval in an 8-6 vote. See additional reporting in Nature.

• A fifth clinical trial for base editing is now enrolling patients. It’s a phase I/II clinical trial for people with relapsed or refractory T-cell acute lymphoblastic leukemia.

• Two different gene therapies restored inherited hearing disorders in mice.

• A great article in The New Yorker that I highly recommend: “When Dying Patients Want Unproven Drugs,” by Gideon Lewis-Kraus.

• A CAR-T cell therapy for relapsed or refractory B-ALL targets both CD19 and CD22. Nearly 76% of patients who were given the therapy had progression-free survival at 12 months, compared to 49% in the standard care group. Most patients had serious side effects, though. The clinical trial included 419 patients, 208 of whom received the cell therapy.

• Detect-seq is a method to measure off-target genome edits caused by base editors. It takes 5 days of work, but looks like a useful tool.

• A base editor was used to treat phenylketonuria — a genetic condition that causes phenylalanine amino acids to build up in the body to dangerously high levels — in mice. The animals had a common disease variant, caused by a single amino acid substitution in the phenylalanine hydroxylase enzyme. After base editing, levels of phenylalanine in their blood fell to normal levels within 48 hours.

• Base editing was used to create universal, or “off-the-shelf,” CAR-T cells to treat relapsed childhood T-cell leukemia. The first trial patient, a 13-year-old girl, had remission within 28 days, despite some serious side effects.

• Engineered AAVs pass through the blood-brain barrier in mice, rats, and non-human primates. A big step forward for gene therapies that target the brain.

15 of 30. In 1971, Stanford students frollicked in a field to depict the intricate workings of protein synthesis. Future Nobel Laureate, Paul Berg, narrated the video, which quickly became a cult classic moment in molecular biology history.

Shortly before Berg’s death, in February, the Stanford Medicine Magazine published a story about the dance and where the idea came from. When Berg read a draft of the magazine story, in December 2022, he replied in an email:

I learned a great deal on reading it and relived some of the excitement of doing the project. … There was a time when the film was being shown in biology courses from middle school to graduate courses in genetics and biochemistry and even in post graduate education lectures to physicians. It was reviewed in Nature magazine for its educational value but never for its novelty and pure spoofiness.

16 of 30. There has been some juicy drama in the synthetic-embryos-made-from-stem-cells race. Antonio Regalado, a writer at MIT Technology Review, wrote up a recap of the events. But here’s the basic gist:

1. A bunch of scientists show up to a conference, the International Society for Stem Cell Research, in Boston.

2. A stem cell researcher, named Magdalena Zernicka-Goetz, says that her lab had made a “human embryo model, capable of developing in the laboratory to a stage equivalent to 14 days,” from stem cells, according to reporting in El País.

3. The Guardian publishes a sensationalized story about the claim: “Synthetic human embryos created in groundbreaking advance.”

4. Other scientists push back. From Regalado:

   A Spanish scientist, Alfonso Martinez Arias, quickly launched a campaign on Twitter in which he fiercely denounced “fake news” and “post-truth” science. In reality, he says, Zernicka-Goetz had produced blobs he calls “weakly organized masses of cells” with limited similarity to real embryos.

5. Zernicka-Goetz joins the Twitter parade:

   In response to recent media on my group’s research, I would like to clarify that our goal was not to make headlines but to share our research with the community. We cannot control how the news reports our discoveries, but we are grateful for the interest & constructive comments.

6. Meanwhile, Jacob Hanna’s lab in Israel actually did make “extremely realistic synthetic embryo models that were grown to a stage of around 14 days,” writes Regalado. “According to Arias, Hanna ‘showed exactly’ what Zernicka-Goetz had claimed ‘but hadn’t done.’” 

7. On June 24, Carl Zimmer publishes a story in The New York Times, claiming that four different labs had “coaxed human stem cells to organize themselves into embryo-like forms.”

Here is an excellent write-up (as always) about these “embryo-like” structures, and what they mean, from Quanta Magazine.

The Roots of Progress

The history of technology and the philosophy of progress—a digest of posts from rootsofprogress.org

By Jason Crawford

17 of 30. Jason Crawford, at Roots of Progress, wrote an intriguing thread about hype in biotechnology and why he’s personally “reluctant to share/amplify stories about supposed breakthroughs.” I recently met Jason for coffee at MIT, and I agree with much of what he says.

“Real breakthroughs are pretty rare. And in science, they usually don't come from a single study,” he writes. “They are the accumulation of many studies, over decades—and the consensus builds gradually.”

Crawford points to a recent study that used AI to discover a new antibiotic against A. baumannii, a type of microbe that sometimes causes deadly infections. I covered that paper in this newsletter, but readers pointed out that we can already find new antibiotics with existing technology. Economic incentives, rather than scientific toolsets, are the real problem. But many news websites, including the BBC, ran somewhat sensationalized headlines, such as “New superbug-killing antibiotic discovered using AI,” without mentioning this nuance.

I’ve moved away from covering individual articles in my own writing for a few reasons:

• Often, the back story of a paper is more interesting than the paper itself.

• Readers seem to heavily favor conceptual essays over single-study stories.

18 of 30. I’m posting about a “good” (it’s subjective) biology paper on Twitter every day for 30 days. My experiment is going better than expected, at least in terms of engagement. A couple of takeaways:

1. Nothing is inherently obvious. If you’re a scientist, and you’d like to write, it’s easy to resort to jargon. It’s easy to assume that your readers will know what a gene therapy or AAV or base editor is (hell, I’m guilty of that, too!) But many of them won’t. No reader will ever know all of the things that you know. No reader will (probably) be as excited about the things that you’re writing as you are. That’s because nothing is inherently obvious. If you want somebody to give a damn, you need to very carefully explain why they should.

2. Start at zero. Just because a scientific idea is well-known does not mean it isn’t interesting. If there was a moment in time when you first heard about a thing — a bee carries 35% of its bodyweight in pollen! — and you thought, “Wow, that’s super interesting!” then others will also find it interesting, even if it now feels mundane to you.

19 of 30. On 16 June, I hosted a Tappy Hour with Homeworld Collective, a climate biotechnology nonprofit. A writing workshop was followed by pizza and rosé. Thanks to everyone who showed up.

I recently launched weekly office hours, too. If you would like feedback on a draft, or just want to talk about words, please send me a message. For writing inspiration, also check out this website — Read Something Wonderful — which curates essays from around the web. I have been reading one essay from the list every day.

And finally, this lecture on “The Craft of Writing Effectively” by Larry McEnerney at the University of Chicago is superb.

20 of 30. @plasmidsaurus

@arjunrajlab (Regulation in biology is incredible. And complicated.)

21 of 30. Codon Prize Winner #3: BioConceptVec Explorer

A project by Daniel George, Shrey Joshi, and Shahar Bracha.

Of the three winners, this team is tackling the most difficult problem: How does one find good ideas?

Knowledge is continuous, but its representation in papers is discrete. Every published paper (more than 1.8 million each year) is an individual node on a graph. If you put all the points together, they should add up to the sum total of human knowledge. But they don’t. That’s because knowledge is inherently fluid, and there are discoveries waiting to be found in the interstitial spaces between papers.

The BioConceptVec Explorer is designed to solve this. It uses a model from a 2020 paper, which was trained on 30 million biology PubMed abstracts, to extract concepts (genes, animal species, diseases, drugs) and embed them as vectors. One can then mix, match and combine embedded concepts to uncover new hypotheses. Let me explain.

Each scientific hypothesis is represented as an equation that describes the relationships between biological concepts. The equation “King - Man + Woman” gives “Queen”. Similarly, if you were to type “Carcinoma - Epithelial Cells + Red Blood Cells” into this tool, it would output “Leukemia.”

A demo of this tool, available online, proposes a sensible research idea perhaps 10% of the time. But this approach isn’t hopeless. A 2019 Nature paper used a nearly identical tool to discover a new antiferromagnetic material.

The tool’s utility may also stretch beyond science, and into the realm of writing.

Imagine that you had a digital wall, covered in Post-it notes, and each note has a single idea that is dear to you. My notes might say things like George Orwell, history of science, gene circuits, and Marcus Aurelius.

Now imagine that a benevolent machine could look at all these notes — all the pieces of knowledge and all the ideas that you’ve encountered in life — to find unexplored areas that you will also find interesting. Such a tool could help writers come up with their next story ideas by sifting through scribbled notes, photographs, and recorded conversations. It could suggest ways to compose these scattered notes into a coherent narrative, or it could direct the writer to new sources of inspiration to fill gaps in the story.

I find all of this a bit disconcerting. Perhaps in ten years, me and my words will be obsolete. Perhaps there will be no point in writing anything. I hope that doesn’t happen, and I don’t think it will. But if it does, I’ll be just fine. I’ll move to a log cabin, deep in the Vermont woods, and take a break for a few years, or decades. My digital avatar will persist as a solitary node within the dense, interconnected web of our Human Databank.

22 of 30. The “Lab Leak” theory is back in the news. The Wall Street Journal published an article on 20 June that said a prominent Chinese scientist, working on a coronavirus project funded by the U.S. government, was one of three researchers who fell ill in the early days of the pandemic. The next day, on 21 June, The New York Times said that “intelligence officials determined that the sick workers could not tell them anything about whether a lab leak or natural transmission was more likely,” and so the intelligence community dismissed the news back in August 2022. Neither report claims that any of these researchers were Patient Zero. (See this Twitter thread for more notes.)

Speaking of biosecurity, Decoding Bio recently published a report highlighting the Biosecurity and Biodefense industry landscape. There are many companies on that list that I had never heard of.

And meanwhile, at MIT, students were asked to use LLM chatbots to design a pandemic pathogen. From the paper:

In one hour, the chatbots suggested four potential pandemic pathogens, explained how they can be generated from synthetic DNA using reverse genetics, supplied the names of DNA synthesis companies unlikely to screen orders, identified detailed protocols and how to troubleshoot them, and recommended that anyone lacking the skills to perform reverse genetics engage a core facility or contract research organization.

Responses to the paper were mixed.

“Is the LLM really the democratising force here?” wrote Patrick Kearns, a PhD student at the University of Edinburgh. “Anyone with a few years of molecular biology training could do this if so inclined.”

Michael Specter, a New Yorker staff writer, replied. “I co-teach the MIT course and did the study,” he wrote. “Of course, many already have the ability to do harm with biology. Few ever would. But LLMs will greatly increase the number of people who could make or distribute a virus. Seems worth trying to prevent.”

23 of 30. A gene therapy prevents pregnancy in cats. Scientists from the Cincinnati Zoo and Harvard Medical School used AAV9 to deliver and express a gene encoding the AMH hormone in six cats. A single shot prevented pregnancy for two years. A couple of the cats mated with male cats but never ovulated. The other cats never even tried to mate.

The thing that stood out about this article, for me, was not the gene therapy. Or the cats. It was that The New York Times covered such a tiny study at all, and yet didn’t cover…*waves arm*…so many other things. I am unable to find a single news story from them, for example, about the recent F.D.A. approval of Sarepta’s gene therapy for muscular dystrophy. And that, to me, seems far more important than a tiny study in cats. But hey, novelty sells more than importance.

24 of 30. It takes a few minutes to make one protein from one strand of mRNA. A new technique can image and record videos of single mRNAs as they are translated by ribosomes. And the videos can go on for an hour or more, which means it’s possible to watch ribosomes latch onto the mRNAs again and again and again. Brilliant stuff. The red spots are individual mRNAs and the green bits are active translation sites. The video above is from Livingston N.M. et al. in the journal Molecular Cell.

25 of 30. The ribosome makes proteins from twenty different building blocks, called amino acids. But there are 64 codons in DNA. Many codons encode the same amino acid (GCU, GCA, and GCG all encode alanine.) There is really no reason why we couldn’t engineer the ribosome to build proteins from more than twenty amino acids.

But here’s the problem. Each amino acid is carried to the ribosome via a “charged” tRNA molecule that is specific for that amino acid. Enzymes called aminoacyl-tRNA synthetases grab onto an amino acid molecule and then pass them onto a tRNA, which then carries the amino acid to the ribosome. Expanding the genetic code to accommodate more than 20 amino acids is difficult because there aren’t enough tRNA:aminoacyl-tRNA synthetase pairs. That’s the gist.

In a new paper, though, Jason Chin’s group at the University of Cambridge blew this idea out of the water. Prior studies had shown that it’s possible to add one or two synthetic amino acids to a protein. But Chin’s team discovered five pairs of tRNA:aminoacyl-tRNA synthetase pairs that can be used in living cells. And they didn’t just do it once; they did it eight times. These pairs are orthogonal to each other, too, which means they don’t interfere with one another or with any other cellular processes.

This discovery can be used to add many additional types of amino acids to proteins in living cells. Applications span materials and therapeutics.

(P.S. I tried to join Chin’s lab for my PhD, but was rejected at the final stage. Here is a simplified version of my technical proposal, which I wrote as part of my application.)

26 of 30. A couple great CRISPR gene-editing papers:

• Adenine transversion editors can switch ‘A’ to ‘C’ in DNA with an efficiency of 73 percent and with minimal off-target effects. The editors were tested in mice and human cells, and made the correct edit between 44 and 56 percent of the time.

• RNA-guided nucleases, called HERMES, are common across eukaryotes and the viruses that infect them. These proteins — much like Cas9 — use non-coding RNAs to cleave double-stranded DNA. And they can be used to edit the genomes of human cells. The DNA editing toolbox keeps getting bigger!

27 of 30. Ancient Egyptian monuments in Luxor are covered with fungi and bacteria that slowly eat away the stone. I didn’t know this. But there’s a whole niche community in archaeological conservation that studies whether microbes actually damage stone. And it seems that they do.

So this group of Egyptian researchers did something clever. They swabbed these stone monuments and isolated the fungi and bacteria from their surfaces. And then they found another microbe, called Streptomyces exfoliatus, that produces chemical compounds that kill off some of the stone-eating strains. They want to take these Streptomyces microbes and spray them onto the stone monuments as a sort of “natural” pest control. I’m not sure whether it will work, or if evolution and random mutations will make them last only for a little while, but I like the idea.

28 of 30. Two papers that use light to control biology:

• A plasmid is a loop of DNA that encodes genes. Bacteria use plasmids all the time to swap genetic material. A new study shows that it’s possible to make light-activated plasmids. The way it works is that you take one strand of DNA, from the double-stranded plasmid, and add light-sensitive chemicals, called photocages. These chemicals are inserted into the promoter of the gene, so they block transcription. But when light shines onto the photocage, it is destroyed, and the plasmid switches “on.” (It cannot be turned off.)

• Another great study made light-switchable transcription factors — proteins that bind to DNA and control gene expression — by fusing them to a “photoswitchable” protein domain. The method was tested on a transcription factor, called Gal4-VP64, that activates genes. And it worked. There was a >150-fold change in gene expression between the dark and light conditions.

29 of 30. The Italian transplant surgeon, Paolo Macchiarini, was “found guilty of gross assault against three patients on whom he tested synthetic tracheae” and sentenced to 2.5 years in prison. The Stockholm Court of Appeal “concluded that Macchiarini’s interventions on three patients who later died amounted to serious assault,” writes Marta Paterlini in the British Medical Journal. “Prosecutors in the case said that the interventions could not have been considered medical care and were not consistent with proved scientific methods and therefore could not go unpunished.”

Macchiarini has been convicted of research-related crimes in Italy and Sweden. A decade ago, the Karolinska Institutet physician was hailed as a pioneer in using stem cells to build artificial tracheas that could then be transplanted into patients. Several patients who received a tracheal transplant from Macchiarini later died, and autopsies were not always performed.

The excellent Retraction Watch blog, where I briefly worked while studying at New York University, has been covering Macchiarini since 2012.

30 of 30. “Data-to-paper” is an autonomous AI tool that generates full-length research articles — with an abstract, methods, and discussion section — from a single dataset. Its creators gave it access to a dataset from the CDC and then went to lunch. When they came back, “it had already chosen several research topics, wrote data analysis codes, interpreted results and wrote 5 transparent, reproducible papers.”

Let me be clear: I hate this, and I don’t really give a damn if the 294 people who “liked” this tweet crucify me for it. My hatred isn’t even related to the tool itself. Of course, this was inevitable. ChatGPT can already write entire science news articles, replete with quotes plucked from press releases. Newsrooms are laying off writers as you read this. ChatGPT can already write a crappy abstract or methods section.

This tool might help some scientists write papers faster (most people hate writing!) And yes, a GPT-generated draft would be edited before it’s sent to a journal! But the whole premise is misguided.

We need less formulaic writing in science; not more of it. We need more papers that are beautiful and pleasant to read, and GPT’s eye-blurring prose and formulaic structures will lull weak scientists into bad habits. Paper mills already churn out many thousands of studies each year that are worth little more than the paper they’re printed on. And I think those scientists — not the thoughtful ones — will be the great beneficiaries of AI writing tools.

Also…come on. “Created papers” — generated by the AI tool — “are not perfect. In particular, the statistical tests done by chatgpt can have issues, e.g.: not always correctly controlling for confounding variables.” Sounds like a recipe for disaster.

— Niko McCarty

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

1. That forty years ago, “it took 8,000 pounds of pancreas glands from 23,500 animals to make one pound of insulin,” enough for 750 people with diabetes annually, but now insulin is made by engineered bacteria.

2. That gene-edited hens “lay eggs from which only female chicks hatch,” which could one day keep 7 billion male chicks from the macerator each year.

3. That mosquitoes have killed billions of people across human history and still kill 700,000 people annually, but now we have a malaria vaccine, made by a fungus, that is more than 70% effective.

4. That type A or B blood can be converted to O (universal donor) by using enzymes that chop sugars off cells, and this same technology has been used to convert blood type-A lungs into blood type-O lungs to make “universal donor” organs.

5. That 3,000 Americans are waiting for a new heart, but xenotransplantation — putting an animal heart into a person — is nearly here thanks to “humanized” pig organs depleted of antigens that cause immune reactions.

6. That a hundred years ago, most people with hemophilia died by 13 years of age (at the time, there was no way to store blood, so the only treatment was to transfuse blood from a family member) but now a single injection of a gene therapy, called Hemgenix, can treat people with type B hemophilia.

7. That gene therapies to lower “bad” LDL cholesterol by turning off the PCSK9 gene in the liver could prevent cardiovascular disease for millions of people and have been tested in clinical trials in New Zealand and in monkeys.

8. That multiple myeloma, a white blood cell cancer, has a five-year survival rate of 58%, but a recent clinical trial that treated people with genetically ‘rewired’ immune cells tripled the time it took for cancer to progress, from 4.4 to 13.3 months.

9. That pancreatic stem cells, transplanted into the body, can restore insulin levels and, in some cases, have helped people with diabetes go years without injections.

10. That in vitro fertilization can help people suffering from infertility have children, and same-sex couples may soon be able to do the same by reprogramming their stem cells into eggs. 

11. That the COVID vaccines were made in one year, partly because scientists mapped the viral genome and shared it online in early January 2020, and the prior vaccine speed record was four years, for a mumps vaccine back in the 1960s.

12. That chemical space exceeds 10⁶⁰ molecules, but a screen of one million molecules still produces drug target “hits,” which means that life (fortunately) exists within a small window of molecular possibilities and drug discovery is not a hopeless endeavor.

13. That microbes on telephone poles and handrails around New York City (and lots of other places) make thiocillin antibiotics that kill normally-resistant bugs, and our present dearth of antibiotics stems from poor economic incentives, rather than a true lack of drug options.

14. That gene-edited microbes can convert industrial emissions from steel factories into acetone and isopropanol in a carbon-negative process and at commercial scales.

15. That all life shares DNA as a language, meaning genes from daffodils and microbes can be inserted into rice to coax the plants into making provitamin A, a molecule that could save the lives of thousands of malnourished children each year.

16. That crop yields have roughly tripled over the last 60 years and we can theoretically feed 10 billion people with our current food supply, without chopping down any more forests, which is good because as many trees have been lost in the past hundred years as in the nine thousand years prior.

17. That redwood trees grow to 1.4 million pounds of mass and scrub enough carbon from the air to offset my breath for 50 years or more, and gene-edited trees that grow up to 50% faster and eat up to 27% more CO₂ than ‘normal’ trees in greenhouses are now being tested in the real world, too.

18. That Rubisco — which is probably, but not definitely, the most common protein on Earth — is slow at stripping CO₂ from the air, but it’s possible to ‘borrow’ protein domains from a turbocharged Rubisco, found in red algae, to boost the enzyme’s photosynthetic rates two-fold in tobacco plants.

19. That 150 years ago, we didn’t know that microbes cause disease and now we can view atomic-resolution protein structures on an iPhone. 

20. That deep learning models can design proteins that don’t exist in nature, including light-emitting luciferases that are structurally distinct from those found in fireflies.

21. That a green fluorescent jellyfish protein can be fused to other proteins, enabling one to directly observe molecules move through cells, unravel how nerves grow in the brain, or map how cancer spreads through the body.

22. That neurons in the brain or eye can be controlled, with sub-second temporal and sub-millimeter spatial resolutions, using pulses of light or sound, and this has been used to restore sight in people with specific forms of blindness.

23. That digital data can be stored on DNA at a theoretical density of 455 exabytes per gram, which means a coffee mug filled with nucleic acids could store all the data produced in the last two years.

24. That cheap DNA sequencing is unearthing ancient human history in the absence of written records, deciphering how our species lived and ate by reading the genetic material found in ancient bones or the counters of 2,000-year-old Roman fast food restaurants.

25. That DNA editing, gene therapies, and most of the wondrous things in biotechnology are mere adaptations of nature, and there is still plenty of room at the bottom.

This blog was co-authored by Avadhoot Jadhav. Thanks to Tom Ellis, Dan Goodwin, Tony Kulesa, and Paul Reginato for suggestions.

Subscribe now

Note from our sponsor: Fifty Years supports early-stage founders solving the world’s biggest problems. Their Fifty 50 program teaches entrepreneurial PhDs/postdocs in Bio or Climate everything they need to start a company. If you know someone who could be a fit, nominate them.

Note: My work at MIT and Asimov has picked up significantly (in exciting ways that I’ll write about soon!), so this Digest will be published more irregularly. Thanks for reading.

This week: A way to measure a transgene’s expression in the brain using ultrasound, a DNA sequencing method that uses 1000x less reagents, and base editors get even smaller.

Let’s dive in.

A note from our sponsor:

Our friends at Fifty Years are the best at helping world-class scientists become world-class entrepreneurs. They believe a key to solving the world's biggest problems is helping more scientists translate their work via startups. If you're thinking of starting a startup, reach out to them at codon@fiftyyears.com. Fifty Years is also proud to sponsor Codon.

🔥 Amazing Things

…that happened this week, in 5 minutes or less.

1/ Deep Learning-Guided Antibiotic Discovery

A new antibiotic kills Acinetobacter baumannii, which is one of three superbugs identified by the W.H.O. as a “critical threat” to humanity. It’s called abaucin.

How? Nearly 8,000 molecules were screened in the lab to find those that inhibited the growth of A. baumannii, a microbe that is notorious for its high resistance to off-the-shelf antibiotics. The screened molecules had known chemical structures, and nearly 500 of them were active against the bacteria. These data were then used to train a message-passing neural network to “predict” which other chemical structures might also inhibit growth of A. baumannii.

The neural network was unleashed on a database of 6,680 compounds with unknown activities and produced a “shortlist” of possible antibiotics in 1.5 hours. Out of 240 molecules on the shortlist that were tested in the lab, 9 inhibited A. baumannii by at least 80%. Abaucin, the winning molecule, was also validated in mice and human samples. It’s highly specific against A. baumannii and doesn’t kill much else.

This new molecule — unlike traditional antibiotics — targets the lipoprotein trafficking system. It interferes with a protein complex, called LolE, that shuttles lipoproteins from the inner to the outer membrane. A single mutation at amino acid position 362 in this protein, though, confers resistance to abaucin.

So What? This paper is amazing, but not unprecedented. Other studies have similarly applied machine learning to antibiotic discovery, including a paper last year that identified antimicrobial peptides in the human gut using deep learning. But this paper seems far more general, and I like that they delved so deep into the mechanism of how the chemical works. I’m assuming it’s now possible to screen lots of molecules against nearly any microbe, and run this neural network to find other narrow-spectrum candidates with high activity. That seems profoundly useful.

Read more in Nature Chemical Biology.

2/ Shrinking Base Editors

IscB is a weird gene-editing enzyme that has low activity in human cells. An engineered version of this protein can convert DNA bases with efficiencies up to 92%. It is, in other words, a new type of miniature base editor.

How? The researchers first compared the editing efficiency of different versions of IscB when coupled with 'ωRNA,' which guides the enzyme to the right spot on the DNA. A particular variant, named IscB*-ωRNA*, had the highest editing efficiency across multiple different sites in the genome.

The protein was fused to an exonuclease, an enzyme that cuts DNA strands. The resulting fusion protein was tested at 23 sites across five genes, and had editing efficiencies up to 22 times higher than wild-type IscB, reaching levels of 61%.

Some versions of IscB can also be converted into base editors. By mutating just three amino acids in the wildtype protein (D61, E193 and H247), the authors made a nickase (it ‘nicks’ DNA, but does not cut it). Then, they generated two types of base editors: One that converts A to G, and another that converts C to T, with editing efficiencies up to 63% and 66%, respectively.

So what? This paper is a big deal! The wild-type IscB protein only has 500 amino acids. Base editors made from Cas9 are about twice as big. This means that IscB base editors might be easier to package inside of AAVs, which can only store 4,700 bases of DNA for gene therapies.

Read more in Nature Methods.

3/ Cell Membrane Editor

A cell is a lipid shell with lots of DNA, proteins, and RNA molecules inside. If I sit down, close my eyes, and think about a cell, I suppose it’d be obvious to think that there must be proteins that ‘tweak’ the shell, convert one lipid into another, make new lipids, and so on. But never, in my three years of writing this newsletter, do I recall hearing about someone who engineered a cell membrane-editing protein to make new types of lipids.

For a new study, researchers engineered an enzyme called phospolipase D (which breaks phosphatidylcholine into a lipid and choline molecule) to be 100-fold more active than its wildtype version, and also to make lipids with designer ‘heads’.

How? Researchers introduced between 5 and 11 mutations in the PLD enzyme to make a series of superPLD variants. Each variant was screened using an in vitro assay.

The resulting superPLDs can catalyze two different reactions: Hydrolysis and transphosphatidylation (exchange the head groups of phospholipids), which means it’s now possible to make a whole slew of natural and unnatural phospholipids with designer chemical groups.

The superPLD enzymes became “fast” thanks to a single structural tweak: A histidine at position 440 shifted into a new position, made a larger catalytic pocket, and could thus more easily take in phospholipid substrates.

So what? This paper is just cool. The engineered enzymes can edit a cell’s membrane to change its stiffness, or to turn living cells into “designer phospholipid” factories. It opens up a whole new class of biological engineering. Cell engineers are often so focused on DNA, RNA and proteins, while neglecting anything related to lipids. Hopefully this paper changes that.

Read more in Nature Chemistry.

🧪 From the Lab

Other wet-lab papers worth checking out. (* = Recommended)

• *Sequencing by avidity enables high accuracy with low reagent consumption. Nature Biotechnology. Read

A DNA sequencing method that saves money by reducing some required reagents by 1,000x. It’s also super accurate.

• *Light-driven biosynthesis of volatile, unstable and photosensitive chemicals from CO2. Nature Synthesis. Read

Some bacteria can convert CO2 to other molecules, but they’re difficult to engineer. This paper presents a modular approach to convert CO2 into olefins and other molecules by assigning different tasks to distinct microbes.

• Biosynthesis of cannabigerol and cannabigerolic acid, the gateways to further cannabinoid production. Synthetic Biology. Read

This is fun (but not unprecedented). By taking enzymes from Cannabis sativa and repurposing them, it was possible to synthesize cannabigerols in E. coli cells.

• Development of a chemogenetic approach to manipulate intracellular pH. JACS. Read

A new method to control pH inside a living cell using engineered enzymes and pulses of light.

• *Spontaneously established syntrophic yeast communities improve bioproduction. Nature Chemical Biology. Read

• *Acoustically-targeted measurement of transgene expression in the brain. bioRxiv. Read

• *An engineered influenza virus to deliver antigens for lung cancer vaccination. Nature Biotechnology. Read

• *Stoichiometric expression of messenger polycistrons by eukaryotic ribosomes (SEMPER) for compact, ratio-tunable multi-gene expression from single mRNAs. bioRxiv. Read

• *Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum. Nature Communications. Read

• Strand-selective base editing of human mitochondrial DNA using mitoBEs. Nature Biotechnology. Read

• Meningococcal ACWYX conjugate vaccine in 2-to-29-year-olds in Mali and Gambia. NEJM. Read

• A fully integrated wearable ultrasound system to monitor deep tissues in moving subjects. Nature Biotechnology. Read

• Walking naturally after spinal cord injury using a brain–spine interface. Nature. Read | News

• Improving the soluble expression of difficult-to-express proteins in prokaryotic expression system via protein engineering and synthetic biology strategies. Metabolic Engineering. Read

• A non-transmissible live attenuated SARS-CoV-2 vaccine. Molecular Therapy. Read

• Synthetic virology approaches to improve the safety and efficacy of oncolytic virus therapies. Nature Communications. Read

• Programming inactive RNA-binding small molecules into bioactive degraders. Nature. Read

• Synthetic biology pathway to nucleoside triphosphates for expanded genetic alphabets. ACS Synthetic Biology. Read

• Engineered bacteria to accelerate wound healing: an adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial. eClinicalMedicine. Read

• Gene expression dynamics in input-responsive engineered living materials programmed for bioproduction. Materials Today Bio. Read

• Living microecological hydrogels for wound healing. Science Advances. Read

• Maximizing protein production by keeping cells at optimal secretory stress levels using real-time control approaches. Nature Communications. Read

• Modular metabolic engineering and synthetic coculture strategies for the production of aromatic compounds in yeast. ACS Synthetic Biology. Read

• Spatial imaging of glycoRNA in single cells with ARPLA. Nature Biotechnology. Read

• Genetically encoded photocatalytic protein labeling enables spatially-resolved profiling of intracellular proteome. Nature Communications. Read

• An RNA origami robot that traps and releases a fluorescent aptamer. bioRxiv. Read

• Cultured meat platform developed through the structuring of edible microcarrier-derived microtissues with oleogel-based fat substitute. Nature Communications. Read

• A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder. Nature Communications. Read

• Intracellular RNA and DNA tracking by uridine-rich internal loop tagging with fluorogenic bPNA. Nature Communications. Read

• A noncommutative combinatorial protein logic circuit controls cell orientation in nanoenvironments. Science Advances. Read

💾 Computers x Bio

Papers from the worlds of AI & programming. (* = Recommended)

• *An all-atom protein generative model. bioRxiv. Read

• *Global analysis of the yeast knockout phenome. Science Advances. Read

• *MISATO - Machine learning dataset of protein-ligand complexes for structure-based drug discovery. bioRxiv. Read

• Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nature Biotechnology. Read

• Inference of cell type-specific gene regulatory networks on cell lineages from single cell omic datasets. Nature Communications. Read

• FLUXestimator: a webserver for predicting metabolic flux and variations using transcriptomics data. Nucleic Acids Research. Read

• ExpressAnalyst: A unified platform for RNA-sequencing analysis in non-model species. Nature Communications. Read

📈 Data Brief

One chart about biology and our world.

Malaria deaths plummeted between 2010 and 2015, thanks mostly to the billions of dollars in philanthropic funding that were used to purchase bed nets and medicines. Most deaths are in children under 5 years, and the first vaccine to get endorsed by the WHO for “broad use” in this age group was Mosquirix…in 2021.

Only about 1.5 million children have received this vaccine so far, and the rollout is far from simple. Infants need at least three doses before age 2, and the vaccine only reduces severe cases by about 30%. The good news, though, is that many more vaccines are on the way. R21, developed at the University of Oxford, was up to 80% effective in a small clinical trial of 450 children in Burkina Faso.

Mosquitoes kill more humans, by far, than any other animal. Combatting malaria, dengue, and other diseases will be the great medical achievement of our generation. We are living through history.

📤 In the News

Rapid-fire news items you might have missed.

• Why is it so difficult to make gene-edited rice? Well, it doesn’t help that a single experiment can take 3+ months! My essay for Works in Progress magazine. Read

• Asimov, a company that builds tools to program living cells, launched an engineering blog. I’m writing some of them and I hope you’ll subscribe. Read

• Heartcore Capital released their AI & Productivity Report, which touches on how AI is shaping software, biotech, and some other fields. I wrote a blurb for it. Read

• People with brain implants, who later have them removed, feel worse off. As Neuralink, Paradromics and other brain:machine interface companies raise money and put implants into people, we’ll hear much more about this issue. MIT Technology Review. Read | Read

• A tablet version of semaglutide, the weight loss drug, helped people shed 15.1% of their body weight (compared to 2.4% on placebo) over 17 months. No more injections. STAT. Read

• We’re super close to making eggs or sperm by reprogramming other cells in the body. It’d be a big deal for IVF. NPR. Read

• A curated list of AI resources from a16z. Recommend. Read

• The F.D.A. needs more time to decide whether or not to approve Sarepta’s gene therapy for Duchenne muscular dystrophy. (An advisory panel recommended approval in a contentious 8-6 vote.) Fierce Biotech. Read

• U.S. lab in Kansas will work with deadly animal pathogens. Science. Read

• Neuralink says it has F.D.A. ‘OK’ to start clinical trials. Ars Technica. Read

• Opentrons is releasing a new line of AI-compatible pipetting robots. Read

• GenScript says they can synthesize more challenging DNA sequences between 200 and 1,800 base pairs in length. Read

• Synthace now integrates ChatGPT with their lab automation platforms. Scientists can “use a natural language interface to describe their intent, use the AI to design complex experiments, and then run those experiments on lab equipment.” Read | Video

• HuidaGene Therapeutics, a Chinese gene-editing company, says they have developed the first DNA base editor that can convert guanine to cytosine or thymine. Labiotech. Read

• Novartis bought a blood stem cell gene therapy program for $87.5 million in cash. Labiotech. Read

• VarmX raised €30M to run a clinical trial for blood clotting. They make a drug, called VMX-C001, that is a recombinant form of blood clotting factor X protein. Labiotech. Read

• ReNAgade Therapeutics raised a $300M Series A. The RNA therapeutics space is flourishing in a time of otherwise tight finances. STAT. Read

  • The next day, ElevateBio raised $401M. They make gene editors. Fierce Biotech. Read

🧠 Musings

Fun stuff that has little to do with biotech.

• ChainForge is a visual environment for prompt engineering. Recommend. Read

• An excellent essay about Thomas Edison, and why he was brilliant despite the criticisms. “He took tech that barely worked and made it useful. He took products to market at prices people were willing to pay. He made things that could be manufactured at scale. He hit deadlines.” By Eric Gilliam for Works in Progress. Read

• “Graduate students report anxiety and depression at rates six times that of the general population,” according to data from 2,300 respondents in 25 countries. The numbers are worse for women. Nature. Read

• Remember that famous picture of Ben Franklin holding a kite during a thunderstorm? Yeah, it’s all made up. It shows Franklin’s son as a young boy, but he would have been 21 at the time. And Franklin did the experiment while standing under shelter. Ars Technica. Read

• Nanoparticles are now the world’s lightest paint; no pigments needed. Ars Technica. Read

• Compostable plastic cups are often made from polylactic acid, or PLA. They’re touted as being ‘green,’ but don’t break down in seawater even after 14 months. New Scientist. Read

• A device turns breast milk into freeze-dried powder. Tech Crunch. Read

⚒️ In the Ether

Education, resources, and events.

• The BioxML hackathon is happening this week. The demos are this Sunday, June 4th! View more

• Fifty 50 is a free program for PhDs and postdocs who want to start a company. (And I’m pretty sure you can nominate yourself.) Apply

• A new game studio is making “Minecraft for synthetic biology.” They’re looking for developers. Read

👀 Meme of the Week

“I booked the FACS from 1pm” @OdedRechavi

Until next time,

— Niko

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

A typical farmer in India makes ₹15,000 per month, or about 180 U.S. dollars. They could make more money by growing hybrid crops, which grow faster and larger than anything else on the market. But the seeds are very expensive. They must be purchased from a large company, such as Syngenta, Bayer, or Biostadt India.

Hybrid rice (the staple crop for half of the world’s population) is often 10-20 percent bigger than even the best inbred strains. In the U.S., more than 99 percent of all corn is hybrid. But in low- or middle-income nations, less than half of farmers can afford to plant these special seeds, which are made by painstakingly taking pollen from one crop and using it to fertilize another.

Hybrid seeds are also only good for one year. They cannot be replanted for a second generation or they lose their vigor. A hybrid’s offspring, often, won’t grow as big because all the ‘good’ genes are washed out and lost.

But change is coming. We are now hurtling toward a future in which farmers could possibly buy hybrid seeds once, and then grow them forever, without relying on the big seed companies at all. It’s called synthetic apomixis.

A small number of plant biologists are making genetically engineered plants that produce clonal offspring without any fertilization. The plants don’t have sex. They just…clone themselves. If we figure this out, it would be possible to fix a plant’s traits in perpetuity, without worrying about messy genetics. It would be possible to make a hybrid plant once, and then propagate its traits forever. In the right hands, this could boost global crop yields and uplift millions of the world’s poorest. It would probably be the biggest agricultural breakthrough since the invention of hybrid rice in the 1970s.

Dandelions and hundreds of other plants naturally do apomixis, but none of the nutritional staples — like rice, corn, or soybeans — do. Mary Gehring, associate professor of plant biology at MIT’s Whitehead Institute, is trying to solve that. We recently sat down to talk about synthetic apomixis and the future of agriculture.

This interview has been edited. Additional notes, my own, are included in parentheses.

Niko McCarty: Hey, Dr. Gehring. It’s hard to understand what the impact of synthetic apomixis might be without first understanding how hybrid seeds are currently produced. Can you explain that process?

Mary Gehring: Many of the seeds that you buy from seed companies are hybrids. It’s easy to make hybrid seeds from some plants, but more difficult in others, depending on where the pollen or female parts are located. Soybeans tend to self-fertilize, so it’s relatively difficult to breed hybrid plants. Rice also self-fertilizes, so it’s tricky. They are fairly expensive to make because you need to make sterile males first, and then breed those with the other female parent, to ensure the plants don’t self-pollinate. 

Niko: Do the big seed companies keep a portion of their crops each year to breed the next generation? How do they maintain all the parental lines?

Gehring: Yes, inbred lines have to be carefully maintained. You need to prevent cross-pollination, and you must be sure of the genetic purity of your line each time you plant it. Inbred lines are maintained by just crossing the same genotype to itself over and over again. And in some species, this will just happen through self-fertilization. A hybrid is created by crossing two different inbred lines.

Niko: Hybrid seeds produce larger plants because of something called hybrid vigor. But what does that mean?

Gehring: There are many, many inbred lines. These inbreds have no genetic variation; there’s no diversity. The two alleles are the same for every gene, so this genotype can be propagated indefinitely if you keep breeding that plant. And just like in animals, an inbred line is generally less vigorous than a heterozygote. Many, many years ago people realized that if you cross two inbreds, the resulting F1 will be more vigorous than either parent. That is hybrid vigor. Hybrid plants are generally larger, more robust, more resistant to stresses, and will typically have higher yields.

Niko: Got it.

Gehring: But then, if you take that hybrid plant and self-fertilize it, the progeny will lose this vigor. There'll be a segregation of traits, where some plants are vigorous, like the parent, but some will be more like the inbred grandparent, and some will be even worse than that. Uniformity is generally desired for agriculture. But if you take the progeny of a vigorous hybrid, you would just have this diversity of plant phenotypes, many of which would be negative.

Niko: Ahh, I see. So that’s why big agricultural companies keep generating these hybrids and selling the seeds?

Gehring: Exactly.

Niko: Now tell me about synthetic apomixis. How would it change how hybrid plants are made today? 

Gehring: Right. The idea is this: If you could engineer seeds so that they reproduce asexually, then you could pass on the vigorous genotype year after year. You could breed a hybrid plant that's really good for a specific region, and then maintain its traits without having to generate that same hybrid over and over again.

Niko: Do seed companies want to stop research on apomixis? Are they concerned that it could slash into their monopoly on seed supplies? 

Gehring: No, I mean, I think companies are actually interested in apomixis because it would make breeding programs so much faster. If you can transmit a genotype without recombination, then that is also good for seed companies because it takes so long to breed plants currently.

Niko: What is the current state of synthetic apomixis? What do we still have to figure out? 

Gehring: Yeah, I mean, you've probably come across the recent work in rice. (Researchers altered two genes — called MiMe and BABYBOOM1 — in rice to make “hybrid plants that produce more than 95% of clonal seeds across multiple generations.) But there have been a couple of exciting papers over the past couple years. 

There are three main components of apomixis that we need to figure out. The first step is to bypass meiosis so that you make a gamete and an egg cell that is diploid (maintains two copies of each chromosome.) It basically is like a mitotic cell rather than a product of meiosis. 

Second, you have to get that diploid cell to make an embryo without fertilization, without the addition of sperm. The third component, which is probably the most complicated and where there's the least progress, is to make the embryo’s nutritive tissue, the endosperm, without fertilization.

Niko: Why is the endosperm important? 

Gehring: Well, the endosperm is the part of the plant that we eat. And so the properties, the quality of endosperm, is very important. If your hybrid gives you a particular endosperm quality or phenotype, then you wanna be able to maintain that.

Niko: Got it. And so what have recent papers shown, at least for those first two steps?

Gehring: Well, this really exciting paper came out in rice this year. It showed that they could bypass meiosis in rice to make this diploid egg cell, and then they could induce parthenogenesis (develop an embryo from an unfertilized egg cell) in a hybrid plant. They showed that they could transmit that hybrid phenotype. But the third piece was missing. The endosperm was still a product of sexual fertilization.

Niko: The amazing thing about that paper, from what I understand, is that the engineered hybrid plants produced more than 95% clonal seeds, and they did it across three generations. Is that good enough for the seed companies? Do we need synthetic apomixis to be 100% efficient?

Gehring: I think 95% is amazing. It’s certainly farther than anything else, but you’d probably have to ask a seed company. If you buy a seed, and 95% of its offspring are clonal, is that good enough for farmers? I'm not an expert in agricultural economics, so I don’t know.

Niko: And the paper only did this in one specific type of rice, right? There are thousands of different rice cultivars grown around the world, and something like 3,000 species of rice in India alone. If we figure out synthetic apomixis in one plant, will it be possible to transfer it to another?

Gehring: Yeah, that's really important. Obviously the more lines you can do this in, the more impact it will have. But my guess is that, once we figure out the key genes for a particular species, it will probably be transferable to other genotypes within that species. I don't think that what we develop for rice, say, will work for soybean. I don't think there's going to be a single solution.

Niko: Do you think in 10 years we'll have this figured out?

Gehring: We will probably have it figured out in a laboratory context within 10 years or less. Getting it to farmers as a commercially viable product will take longer.

Niko: And what happens then? What impact would this have on poor farmers, who currently buy expensive seeds from agricultural monopolies?

Gehring: What I’d say is that this probably is not a magic bullet. The question is: Who has this technology? Will it be open access, or will it be in the hands of a company? That’s going to impact how this gets distributed throughout the world. In an ideal world, it would help poor farmers, but I don’t know if that will actually happen.

But synthetic apomixis does have the potential, still, to make agriculture require less inputs and be more resistant to climate variability, because of the vigorous nature of hybrids. Right now, hybrid seeds are too expensive to buy in some cases, right? But if poor farmers could get their hands on hybrid seeds with these traits, they could keep propagating them. So this could still help in places with fewer resources.

Thanks to Will Shaw and Alice Boo for helpful discussions.

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

Let’s dive in.

A note from our sponsor:

Our friends at Fifty Years are the best at helping world-class scientists become world-class entrepreneurs. They believe a key to solving the world's biggest problems is helping more scientists translate their work via startups. If you're thinking of starting a startup, reach out to them at codon@fiftyyears.com. Fifty Years is also proud to sponsor Codon.

🔥 Amazing Things

Biotech highlights in 5 minutes or less.

1/ AI Agents Design Proteins

An automated platform, called Self-driving Autonomous Machines for Protein Landscape Exploration (SAMPLE), can design and build proteins using intelligent agents and robotics. In an initial proof-of-concept, it was used to make glycoside hydrolase (sugar-cutting) enzymes that can withstand higher-than-normal temperatures.

How? The SAMPLE system used four different autonomous agents, each of which designed slightly different proteins. These agents search the fitness landscape for a protein and then proceed to test and refine it over 20 cycles. The entire process took just under six months. It took one hour to assemble genes for each protein, one hour to run PCR, three hours to express the proteins in a cell-free system, and three hours to measure each protein’s heat tolerance. That’s nine hours per data point! The agents had access to a microplate reader and Tecan automation system, and some work was also done at the Strateos Cloud Lab.

So what? Agents are taking off fast in biology. These ones use Bayesian Optimization to design and make sugar-cutting enzymes that could tolerate temperatures 10°C higher than even the best natural sequence, called Bgl3. The agents weren’t “told” to enhance catalytic efficiency, but their designs also had catalytic efficiencies that matched or exceeded Bgl3.

Just a few weeks ago, another group merged GPT4 with a pipetting robot and used it to synthesize different molecules. At the time, I wrote: “This looks like an early step toward a much different future for biology: One in which natural language is used to design experiments, program robots, and automate experiments in high-throughput. What appears simple now will be much more complex in one years’ time.”

Obviously, I was wrong. I should have said months.

Read more in bioRxiv.

Correction: An earlier version of this text said “AI agents,” which is only sorta true. They’re Bayesian Optimizers — often used in applied machine learning — with access to robots. Just a semantic clarification.

2/ Epigenome Editing Cuts Cholesterol

A variant of CRISPR technology that does not cut DNA, but rather silences genes by adding methyl groups to them, significantly reduced "bad" cholesterol in monkeys by more than 50%. Tune Therapeutics reported the results last Friday at the ASGCT conference in Los Angeles. This is the first case of CRISPR epigenome editing in a non-human primate. It’s a big deal.

How? Epigenome editors can add methyl groups to DNA, which silences their expression in living cells. I’m not 100% sure how Tune Therapeutics does this, but co-founder Charles Gersbach and others have shown that a ‘dead’ Cas9 enzyme, fused to a DNA methyltransferase, can add methyl groups to DNA in mice. These tools do not cut or nick DNA, and so they may be safer than other options.

For the Tune data, an epigenome editor was used to alter a cholesterol-associated gene, called PCSK9, in five cynomolgus monkeys. This gene is shared by monkeys and humans and, when it’s mutated in juuuust the right way, can lower LDL and reduce heart disease risk.

So what? Again, this is a big deal. Verve Therapeutics is using base editing to go after the same gene and, back in 2021, reported “that one-time editing of the PCSK9 gene in the liver of monkeys lowered blood levels of the resulting PCSK9 protein by 89% and dropped LDL cholesterol levels by 59%, reductions that endured as far out as six months,” according to an article in STAT. Verve already started a Phase 1b trial in New Zealand last July. Tune’s epigenome tool seems to work just as well, but it may be safer (the F.D.A. halted a Verve trial in the U.S. in December, but did not explain why.)

Read more in STAT.

3/ Important Work on Non-Model Microbes

A new toolkit can help identify functional origins of replication, or ORIs, in non-model bacteria. ORIs are where DNA replication begins. Plasmids that don’t contain the correct ORI won’t get copied, so it’s really important to figure out this sequence for every organism that you want to engineer! The toolkit, called Possum, worked in 7 out of 12 species, including extremophiles.

How? The team made a large library of plasmids (192 in total) that contain 22 different ORIs and 20 antibiotic resistance markers. These plasmids were inserted into each microbe via conjugation. Each microbe was then killed and its DNA sequenced. If a microbe had “significantly higher” levels of DNA — a sign that the plasmids were being copied — compared to a negative control, then it suggests that the conjugated plasmid had the correct ORI for that organism. This technique was used to quickly test 374 different microbe-plasmid combinations.

So what? This toolkit is a simple way to figure out ORIs for organisms that don’t have a known replication sequence. It’s also an important first step toward engineering more non-model microbes, which often have super-unique metabolisms. Some “electroactive” bacteria can even make or consume electricity. It’d be cool to genetically engineer them!

Read more in bioRxiv.

🧪 From the Lab

Other wet-lab papers worth checking out. (* = Recommended)

• *A temperature-sensitive genome-editing tool — which uses Cas9 — enhances adoptive T-cell therapy upon mild heating. Nature Nanotechnology. Read

• *A feedback system controls the relative populations of microbes in a community. bioRxiv. Read

• *Engineered bacteria make proteins that carry nitro (-NO2) chemical groups. This is very difficult to do. Nature Chemical Biology. Read

• Microscopes reveal that a transcription factor, bound to DNA, can activate the gene within a few seconds. bioRxiv. Read

• By putting human liver cells into a mouse, scientists figured out how this organ influences the body’s circadian rhythm. Science Advances. Read

• Lipid nanoparticles coated in sugar boost CRISPR-based liver editing from 5% to 61%. Nature Communications. Read

• A new toolkit edits the genomes of five different rhizobacteria that help plants grow. bioRxiv. Read

• Honeybees with engineered microbiomes fight off parasites that contribute to hive collapse. Nature Communications. Read

• Engineered P. taiwanensis make aromatic chemicals with yields of 32.4% from glycerol. Metabolic Engineering. Read

• People that live to 100 have highly diverse viruses in their guts. Nature Microbiology. Read

• CRISPR helps identify essential genes in two different bacteriophages. bioRxiv. Read

• Multiple plants were engineered to make provitamin A carotenoids by endowing them with a metabolic pathway from fungi. Molecular Plant. Read

• Attaching a chemical — called 5-formylcytidine — to guide RNAs changes how they fold and bind to targets during gene-editing. It’s another lever to control CRISPR. JACS. Read

• A chikungunya vaccine induced high levels of neutralizing antibodies in a phase II trial. Science Translational Medicine. Read

• A new protocol explains how to encapsulate proteins and make them more stable for biomanufacturing. Nature Protocols. Read

• A wearable device helps amputees feel heat in their "phantom” hands. Science. Read

• GWAS, CRISPR, and single-cell sequencing were merged to link noncoding genetic variants to blood traits. The study found target genes in 134 regulatory elements across 254 loci. Science. Read

• An intensive study engineered P. putida bacteria to eat D-xylose, a sugar common in plant biomass. bioRxiv. Read

• Prime editing was used to modulate neural circuits and change a mouse’s behaviors. bioRxiv. Read

💾 Computers x Bio

Papers from the worlds of AI & programming. (* = Recommended)

• *DeepBE is a deep learning tool to predict gene-editing efficiencies for base editors and Cas9 proteins. It is 20-fold better than some other models. Nature Biotechnology. Read

• *“How I became myself after merging with a computer.” Brain Stimulation. Read

• AlphaFold can predict protein structures with astonishing accuracy, but we still need actual crystal structures. bioRxiv. Read

• Graphinity, an AI model, predicts the binding efficiency of therapeutic antibodies — with a little help from 1 million synthetic data points. bioRxiv. Read | Thread

• A deep learning tool calculates how mutations in a protein will affect its thermostability. eLife. Read

• Monte Carlo x deep learning were used to design synthetic DNA with specific expression levels. bioRxiv. Read

• A mathematical model controls when, and how much, sugar should be released into a tube of microbes to control their growth rates. bioRxiv. Read

• htFuncLib can design proteins with mutated active sites. It was used to design >16,000 green fluorescent proteins. Nature Communications. Read

• Introme: A machine learning tool to predict gene splicing from coding and noncoding sequences. Genome Biology. Read

• ESP is a machine-learning model to predict enzyme-substrate pairs. Nature Communications. Read

• An open-source workflow to run -omics assays on model organisms. npj Systems Biology and Applications. Read

📈 Data Brief

One chart about biology and our world.

We make a lot of concrete. This is bad.

Between 2011-2013, China made more concrete than America did in the entire 20th century. Today, there are two trucks’ worth of concrete made each year for every man, woman, and child on the planet. Cement production accounts for about 8% of all carbon dioxide emissions. One paper estimates that the entirety of human-created mass (half of which is concrete) probably reached the total weight of Earth’s entire biomass — every tree, bacterium, virus, and whale — in 2020.

If you want to make an impact with biotechnology, materials are a great place to start.

📤 In the News

Rapid-fire news items you might have missed.

• The FDA approved a rub-on gene therapy for dystrophic epidermolysis bullosa, a genetic condition that causes sensitive, fragile skin. MIT Technology Review. Read

  • It costs $24,250 per vial, and patients need about 26 vials per year. That’s $631,000 per year. Read

• For the last two months, Zuzalu has brought together people who think “we have a moral duty to find ways to slow or reverse aging.” They have been living together in Montenegro. It actually sounds great and I hope they do it again. MIT Technology Review. Read

• Scientists are making plants that can effectively clone themselves, which could one day displace the power of monopolistic seed companies. It’s called synthetic apomixis and I’ll have much more to say about it tomorrow. Science. Read

• This is a nice article about the multiplexed genome editing efforts underway in George Church’s lab. The Scientist. Read

• CRISPR was not responsible for the death of 27-year-old Terry Horgan in a recent gene therapy trial for Duchenne muscular dystrophy. STAT. Read

• A CRISPR tool that adds methyl groups to DNA — called an epigenome editor — effectively silenced the PCSK9 gene in monkeys and lowered their cholesterol levels. An important proof-of-concept for human trials. STAT. Read

• A neurotechnology company, Paradromics, will get expedited reviews from the F.D.A. and also closed $33 million in funding. Their device is designed to help paralyzed people communicate. Another company, Synchron, is already in advanced clinical trials. Fierce Biotech. Read

🧠 Musings

Fun stuff that has little to do with biotech.

• A crystal cooled to near absolute zero has the minimum amount of possible vibration: one phonon. It is the quietest sound in the universe. WIRED. Read

• Fermented coffee apparently tastes like raspberries. Ars Technica. Read

• The earliest recorded kiss dates back 4,500 years, to a Mesopotamian clay tablet. The Guardian. Read

⚒️ In the Ether

Education, resources, and events.

• Bio x AI Hackathon kicks off on May 26 and runs to June 4. Open to all. Event

• Synthace is hosting a free event at MIT on June 21. Come say hi! Event

• Spira, a company that uses engineered algae to manufacture pigments, is having a free demo in San Francisco on Thursday, May 25th. Event

• The 2023 International Mammalian Synthetic Biology Workshop is on June 22-23 in San Jose. It’s $100 for students. Event

👀 Meme of the Week

See you next week! In the meantime, find me on Twitter or LinkedIn.

— Niko

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

I live in Cambridge. It’s a town that has that quaint-suburb-that-is-still-just-as-expensive-as-the-big-city feel. My apartment is old and kinda spooky, with creaky floorboards and weird nails in the ceiling that I don’t fully understand. The neighbors are great, too. Yesterday, I saw a nice woman sitting outside with her bird while a man, just a bit down the street, donned his boxing gloves and went to battle with a telephone pole.

In this issue: CRISPR’d food is gonna hit U.S. shelves, it’s easy to find DNA in the air, and some weird insect cybernetics.

🔥 Picks of the Week

News highlights in 3 minutes.

1/ First CRISPR’d Food to Hit U.S. Market

Pairwise wants you to eat more mustard greens. Or kale. Or maybe cabbage.

Huh? They’re all basically the same thing?

The company has used CRISPR gene editing to remove the ‘pungent’ smell from mustard greens, which are more nutritious than other salad leaves, like romaine. Pairwise hopes more consumers will eat them if they don’t smell so bad.

The CRISPR’d mustard greens are being rolled out to a handful of restaurants in St. Louis, Minneapolis and Springfield, Massachusetts. Grocery stores in the Pacific Northwest will follow. This is the first commercialized, CRISPR’d food in the United States.

WIRED just wrote a story about this, but it’s sorta old news. Pairwise got the green light from the U.S.D.A. way back in August 2020, and Japan already offers a CRISPR-edited plant in grocery stores: A tomato with boosted levels of GABA, a chemical signal in the brain. "The company behind the tomato, Sanatech Seeds, claims that eating GABA can help relieve stress and lower blood pressure," the WIRED article says.

And the article doesn’t mention how Pairwise engineered the mustard to be “less pungent.” It turns out that mustard greens have an enzyme called myrosinase. The genes that encode this enzyme are spread across seven chromosomes, and there are 17 copies of them. When you chew the leaves, myrosinase makes allyl isothiocyanate, the chemical culprit behind mustard’s punchy taste. (Radish and wasabi apparently have similar molecules.)

Pairwise used CRISPR-Cas12a to knock out all 17 copies of the myrosinase-encoding gene. Anyone who has worked with plants knows that this is an impressive feat. I also found articles that say Pairwise is working on at least 14 gene-edited fruits and vegetables, including blackberries without seeds and cherries without pits.

The company also has licensing deals with Tropic Biosciences to make bananas that don't brown as fast and coffee with naturally low caffeine & high solubility (for instant coffee). To be honest, I don’t fully understand the business decisions behind gene-edited mustard greens. People in the South, at least, seem to like the taste. But I totally understand the push toward bananas that don’t go brown quite so fast; it takes 1.3 kilograms of CO2 and 330 liters of water to make one kilo of bananas, and yet Americans throw away more than 700 million kilos every year.

Read more in WIRED.

2/ Your DNA is Everywhere. And It’s Easy to Find.

A study published Monday in Nature Ecology & Evolution shows that tiny amounts of human DNA, shed into the soil or air, can be easily detected using little more than a $1,000 Nanopore MinION. Researchers figured out a person’s medical conditions and ancestry using dirt collected from a place they had previously visited. That’s scary.

From The New York Times:

As a proof of concept…researchers scooped up a soda-can-size sample of water from a creek in St. Augustine, Fla. They then fed the genetic material from the sample through a nanopore sequencer, which allows researchers to read longer stretches of DNA…

The researchers recovered enough mitochondrial DNA — passed directly from mother to child for thousands of generations — to generate a snapshot of the genetic ancestry of the population around the creek, which roughly aligns with the racial makeup reported in the latest census data for the area…

They also found key mutations shown to carry a higher risk of diabetes, cardiac issues or several eye diseases. According to their data, someone whose genetic material turned up in the sample had a mutation that could lead to a rare disease that causes progressive neurological impairment and is often fatal. The illness is hereditary and may not emerge until a patient’s 40s. Dr. Duffy couldn’t help but wonder — does that person know? Does the person’s family? Does the person’s insurance company?

Scientists need to obtain permission from a university ethics board before they trek out into the woods and search for DNA. Law enforcement officials don’t. They can just do it.

Some of the most interesting details from the paper didn’t make it into the New York Times article, either. Like this one: Researchers recovered strands of DNA that were “up to 148,969 [base pairs] long,” and also found a piece of mitochondrial DNA that was 16,535 bases long, which is “only 34 bp shorter than the full-length mitochondrial reference genome.” DNA from the air gave the longest reads. In other words, you shed DNA all the time, and it doesn’t really break down as fast as you might think in dirt, sand, or the air.

Read more in The New York Times.

3/ How to Stop the Death Cap Mushroom

CRISPR was used to discover an antidote for death cap mushrooms. The approach is clever: Use “CRISPR-Cas9 gene-editing technology to create a pool of human cells, each with a mutation in a different gene.” Then, test “which mutations helped the cells to survive exposure to α-amanitin,” the death cap toxin.

A Chinese group of scientists quickly homed in on an enzyme, called STT3B, that normally coats proteins with sugar molecules. This enzyme is required for α-amanitin’s toxicity. They showed that it’s possible to shut down this interaction via a commercially-available chemical, called indocyanine green, which inhibits STT3B; an antidote.

The Nature article mentions that this approach — mutate a bunch of cells, bathe them in poison, and pull out the cells that survive — had previously been used to discover an antidote for box jellyfish venom. But I also found papers that did the same to discover how Shiga-like toxins and ricin (once used to assassinate a Bulgarian dissident, in 1978) kill cells. Is there anything CRISPR can’t do?

Read more in Nature.

📤 In the News

Other quick-hit news items you might have missed.

• A gene therapy for Duchenne muscular dystrophy is (probably) on the way. But the whole story is weird. On May 12, the FDA said that “the clinical studies conducted to date do not provide unambiguous evidence that SRP-9001 is likely beneficial for ambulatory patients with DMD.” Then — that same day — an advisory panel voted 8-6 to recommend approval for the gene therapy anyway. Oh, to be a fly on the wall. (link)

• Ada Nguyen published a great guide on the longevity biotech landscape. (link)

  • Also in aging news: New Limit launches with $40M. They are mainly using epigenetic editing to explore aging, and how to roll it back. (link)

• Phage therapies — antibiotics’ long-lampooned little brother — are making a resurgent comeback. (link)

• Yup, Elizabeth Holmes is going to prison. Maybe for real this time? (link)

• An mRNA vaccine for many types of flu viruses is now in a phase I clinical trial. If this works, it’s a big deal! No more designing new flu vaccines each year? (link)

• Amgen is sad that the Federal Trade Commission did not let them buy Horizon Therapeutics for $27.8 billion. (link)

• A company that made a chicken breast from fungal proteins is now an XPRIZE finalist and could win the $15M prize. Cool. (link)

• Nicole Paulk, a professor at UCSF and a really successful AAV engineer, just launched Siren Bio. The company will use gene therapies (with engineered viruses) to attack solid tumors. (link)

• Cadence, a company that uses pulses of electricity to alleviate biomarkers of epilepsy, raised a $26 million series B. (link)

• DiogenX, a company that uses a recombinant protein to “regenerate” insulin-producing beta cells for diabetics, raised €27.5M in a series A. (link)

• NewBiologix launches with $50M to manufacture AAVs for gene therapies. (link)

• A Flagship Pioneering company, called Metaphore, launches with $50M to develop drugs based on biomimicry. The whole article is confusing. Read at your own peril! (link)

• Prevail Therapeutics (owned by Eli Lilly) is trying to make genetic medicines for neurological diseases. They’ve now signed a deal for exclusive rights to Scribe Therapeutics’ CRISPR-editing tools. It could be worth $1.5 billion if a bunch of milestones are met. (link)

🧠 Musings

Fun stuff that has little to do with biotech.

• Some fragile scrolls, unearthed from the volcanic ash of Herculaneum after the eruption of Mount Vesuvius, are now being unrolled. Just a few years ago, similar scrolls disintegrated immediately upon being opened. This is part of the $1,000,000 Vesuvius Challenge. For more details on the challenge and why this matters, see the Lunar Society podcast with Nat Friedman. It’s really interesting. (link)

• An interactive “period table of precision fermentation.” Engineered cells are already making vanilla, resveratol, and so much more. (link)

• Ink derived from an octopus can move “dyed particles in response to light,” thus changing colors to match its surroundings. Camouflage. Cool. (link)

• The Netherlands has finally finished building a facility to train scientists how “to prevent, spot and respond to chemical warfare.” The hazmat suits, at least, are hilarious. (link)

• Sydney Brenner was a talented writer. Recommend. (link)

📈 Data Brief

One chart about biology and our world.

In 1990, a four-year-old girl name Ashanti DeSilva became the first person to be cured by gene therapy. DeSilva had adenosine deaminase deficiency, which damaged her immune system and made it difficult to fight off even common infections. Scientists removed Ashanti’s blood cells and inserted a functional copy of the ADA gene via a virus. The blood cells were then given back to DeSilva and, within six months, her immune system returned to normal.

Jesse Gelsinger’s story is more tragic. He died in 2000 after receiving a gene therapy for a rare metabolic disorder. His body “had an intense inflammatory response” and he “developed a dangerous blood-clotting disorder, followed by kidney, liver, and lung failure. Four days after receiving the shot Jesse was declared brain dead and taken off life support.” The clinical trial was halted and 69 others were investigated. James Wilson, director of the institute where the trial took place, was stripped of his titles. Wilson then went on to isolate AAV9 for the first time, and it was later used to develop one of the first FDA-approved gene therapies: Zolgensma.

⚒️ Note of the Week

On companies and underrated ideas.

Put a microchip into an insect cocoon and the butterfly will emerge with electronics hardwired into its brain. (link)

See you next week! In the meantime, find me on Twitter or LinkedIn.

— Niko McCarty

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

This is called the “spotlight effect.” And the reality is this: Everyone has their own life and worries about their own things. Few have time to pay attention to you. Just keep doing what you love.

Now back to the newsletter.

In this week’s update, monkey embryos grow in the lab for 25 days, a suite of papers push prime-editing forward, and a small peptide kills microbes better than most antibiotics.

Let’s dive in!

🔥 Week in Review

Biotech research highlights in under 5 minutes.

1/ Watch Yeast Evolve

I’ve been moderately obsessed with yeast ever since I visited White Labs in San Diego, during a PhD interview at Scripps. White Labs has a little tasting room, and they make some nice beer, but I was there to see something else: Their massive collection of brewing yeast strains, each with a unique fermentation temperature and alcohol tolerance.

Yeast live just about everywhere, and they are remarkably adaptable. Saccharomyces cerevisiae are used to brew beer and are the workhorse for most biologists. But if you make just one change to their genome — a mutation in a gene that encodes a transcription factor, called ACE2 — cells that bud off during division adhere to their mothers. They don’t break off. Over time, chains of yeast begin to form; they resemble snowflakes. A biologist, William C. Ratcliff, figured this out back in 2015.

Now, in a drawn-out experiment that lasted nearly two years, Ratcliff’s group at the Georgia Institute of Technology has shown that these “snowflake yeast” can evolve to become 10,000 times tougher than their ancestors.

How? The experiment is remarkably simple. Every day, for 600 days, a graduate student named Ozan Bozdag went into the lab, took some yeast out of a shaker, and transferred 1.5 milliliters into a tube. After waiting for 3 minutes, they sucked out the top 1.45 milliliters of liquid and left the remaining 50 microliters in the tube. This remaining liquid was used to “seed” the next day’s batch of cells.

By repeating this procedure again and again, the scientists gradually selected yeast that settle fastest to the bottom of a tube. After 200 days, some of the yeast became physically elongated. They became entangled with other cells, much like interwoven threads in fabric — but only when grown in the absence of oxygen!

From The New York Times:

Dr. Bozdag gave oxygen to some yeast in the experiment and grew others that had a mutation that kept them from using it. He found that over the course of 600 transfers, the yeast that lacked oxygen exploded in size. Their snowflakes grew and grew, eventually becoming visible to the naked eye…

…For yeast that could use oxygen, getting large had significant downsides. As long as snowflakes stayed small, the cells generally had equal access to oxygen. But large, dense wads meant that cells within each clump were cut off from oxygen.

Yeast that couldn’t use oxygen, in contrast, had nothing to lose, and so they went big. The finding suggests that feeding all the cells in a cluster is a crucial part of the trade-offs an organism faces as it goes multicellular.

The yeast that “went big” had key mutations across their genomes, including changes in genes linked to the cell cycle and budding. Out of 123 total mutations, 29 were associated with the cell cycle, 11 with cellular budding, and 7 with filamentous growth, or the thread-like extrusions of these cells.

So what? Every science journalist under the sun has covered this paper (though I recommend Ed Yong’s). The paper is also nearly two years old at this point; the preprint was published in August 2021. Hell, the paper isn’t even about biotechnology.

But I’m covering this paper, regardless, because it shows that simple changes at the cellular level can lead to remarkable, biophysical innovation. And it demonstrates — in vivid, visual terms — the remarkable plasticity of life. It proves that even simple experiments — grow some yeast, let them clump, repeat 600 times — can make it into Nature.

There is plenty of room to make discoveries, even with the simplest of tools.

Read more in Nature. See the Twitter thread from Will Ratcliff.

2/ Monkey Embryos Grow to 25 Days

Two Chinese groups published papers in Cell, back-to-back, that show how cultured monkey embryos can be grown in the laboratory, for up to 25 days, in 3-D gels. This is an impressive length of time to develop embryos outside the womb.

The embryos gastrulated, formed a neural plate (the start of a nervous system), and even kicked off the earliest stages of organ formation. There were also “signs that blood cells and their components were beginning to take shape in the yolk sac, which supplies embryos with nutrients,” according to reporting in Nature.

About two years ago, another study in Cell showed that monkey embryos injected with human stem cells — monkey-human chimeras — could develop for at least 19 days after fertilization in the lab.

How? For one of the studies, researchers collected blastocysts from cynomolgus monkeys, the long-tailed macaques native to southeast Asia. The blastocysts were carefully sandwiched between layers of matrigel and Geltrex (a goopy liquid filled with growth factors). Each blastocyst was washed with a TH3, a liquid containing glutamine and pyruvate. On day 9, the cells were fed sugar.

Both of these groups have previously cultured monkey blastocysts for up to 20 days, but then the cells died off. In those earlier papers, it was too early to see organs develop. The cells were also cultured on flat plates, rather than a three-dimensional gel, which restricted their growth.

So What? These experiments could be precursors to studying human development, in the lab, during its earliest stages. But this technique is still a bit unreliable; in one paper, the researchers tested 91 total embryos, just 33 percent of which survived to 20 days.

Read more in Cell. (#1, #2)

(Video credit: Gong Y. et al. in Cell.)

3/ Prime Editing Spree

Prime editors can change DNA in ways that Cas9 — and even base editors — cannot. Known as a "search-and-replace" gene-editing tool, prime editors can delete or replace DNA up to 10,000 bases in length, or substitute one base for another.

Made from a Cas9 nickase (the histidine at amino acid position 840 is swapped for an alanine) fused to a reverse transcriptase enzyme (which makes DNA from RNA; transcription in reverse), prime editing clinical trials are expected to begin by 2025. Early targets may include sickle-cell disease, Friedrich’s ataxia, and cystic fibrosis.

But prime editors also have a couple of issues: They cause some off-target changes in the genome, and they are physically big. It can be hard to get them into cells.

Three studies, from last week, have made the tool better.

PE-tag is a new method that detects off-target DNA changes during a gene-editing experiment. It can do this across the entire genome, using DNA extracted from mice or humans. This tool will be an important tool to ensure prime editors are safe in the clinic, and don’t change random parts of the genome all willy-nilly.

For another study, researchers made mouse models with prime editors encoded in the germline of various tissues. This means that there’s no need to deliver the proteins at all; they are already lurking in the genome. And a third study shows that prime editors can be split up and delivered into cells via two separate viruses. When the proteins are made inside the cells, they click together and edit DNA just like a normal prime editor. This “split” approach was tested in the brain, liver, and hearts of living mice. 🔻

🧪 From the Lab

Other wet-lab papers worth checking out.

* = Recommended.

• *Genomes from 47 ethnically diverse people were sequenced and compiled into a human “pangenome.” Nature. (link)

• *A cell-penetrating peptide, derived from an enzyme that unwinds DNA, cured various bacterial infections in mice. It also outperformed state-of-the-art antibiotics, like ciprofloxacin. EMBO Reports. (link)

• *New base editors can engineer both mitochondrial and nuclear DNA. Molecular Cell. (link)

• *Hypoimmune pluripotent cells were engineered and then used for rejection-free transplantation in primates. This paper paves the way for off-the-shelf cell therapies that don’t require immunosuppressive drugs. Nature Biotechnology. (link)

• A new method releases “trapped” DNA from ancient bones and teeth. Researchers used it to sequence a 20,000-year-old deer tooth pendant. Nature. (link)

• Zebrafish injected with a conductive polymer were controlled with electricity. Preprint. (link)

• A new type of organelle was discovered in fruit flies. It stores phosphate. Nature. (link)

• Genetic circuits that contain interconnected ‘nodes’ are robust against mutations. Nature Communications. (link)

• Engineered Pseudomonas microbes — which eat plant biomass — make isoprenol, a precursor to aviation fuels, with a 3.5 grams per liter titer. Preprint. (link)

• In mice, eight different types of phage (viruses that kill bacteria) were used to clear out E. coli infections and eradicate biofilms. Nature Biotechnology. (link)

• Add long genes to cells with >90% efficiency. Nature Biotechnology. (link)

• A new method compares base editors head-to-head and benchmarks their performances. Cell Systems. (link)

• Machine learning and high-resolution spatial transcriptomics mapped the cells that make up a tumor. Cell Systems. (link)

• INSPECTR is a diagnostic tool to detect tiny amounts of viral RNA at room temperature. From the team at Sherlock Biosciences. Nature Biomedical Engineering. (link)

• An ECoG device was implanted into a pig’s brain through a tiny, centimeter-wide bore hole. Science Robotics. (link)

• A new toolkit uses the Cas3 gene-editing protein to manipulate Streptomyces bacteria. bioRxiv. (link)

• CReATiNG is a technique to build synthetic chromosomes in yeast. bioRxiv. (link)

• An E. coli universal chassis with reprogrammed metabolic flux suppresses overflow metabolism, enhancing the production and yield of chemicals and proteins, paving the way for efficient bioproduction strain design. bioRxiv. (link)

• Administering multiple doses of lentiviral vectors (used for gene therapy) into mouse lungs is better for long-term gene expression than a single dose. Gene Therapy. (link)

• The first-in-human study for RO7122290, a protein designed to stimulate T-cells to attack tumors. Science Translational Medicine. (link)

• Just two enzymes are needed to convert formate, derived from CO2, into formaldehyde in E. coli. This is a key step toward a carbon-neutral bioeconomy. Nature Communications. (link)

• A modified form of two-photon microscopy enables 3D imaging of subcellular dynamics at a millisecond scale, with minimal photobleaching. Cell. (link)

• A phase I trial of a personalized neoantigen vaccine showed that they could boost T-cells and help fight off pancreatic tumors. Nature. (link) (Commentary)

💾 Computers x Bio

Papers from the worlds of AI & software.

• *Foldseek can quickly search through protein structure databases to find what you’re looking for. It is between ten and one-hundred thousand times faster than other leading tools. Nature Biotechnology. (link)

• *Anti-aging compounds were discovered by training a graph neural network to predict which molecules, out of 800,000+, would selectively kill off aged cells. Nature Aging. (link)

• A diffusion model “learned” the distribution of protein structures and then generated novel protein backbone structures with high efficiency. Preprint. (link)

• A deep-learning method predicts which pathogen is likely responsible for a person’s antibiotic-resistant infection before test results are returned. bioRxiv. (link)

• VirPipe is a Python tool to detect viruses from sequencing data. Bioinformatics. (link)

• AOminer is an open Python tool to discover proteins that inhibit CRISPR-Cas gene-editing systems. Bioinformatics. (link)

• TransCRISPR is an online tool to design guide RNAs that target sequence motifs in 30+ genomes. Nucleic Acids Research. (link)

• An open-source R tool visualizes and plots data from microbial genomes. Nucleic Acids Research. (link)

• αCharges calculates partial atomic charges for over 200 million protein structures in AlphaFoldDB, which may help decode their functions. Nucleic Acids Research. (link)

• OnTarget is a webserver to design MiniPromoters, specific DNA sequences that control where a gene is expressed. Nucleic Acids Research. (link)

• MicrobiomeAnalyst 2.0 is a tool to analyze data from microbiome studies. It includes statistical analysis and visualization tools. Nucleic Acids Research. (link)

• EVcouplings is an evolutionary model that can design highly divergent protein variants that have high thermostability and broad substrate availability. bioRxiv. (link)

• scDesign3 is a statistical simulator that generates realistic single-cell and spatial omics data. Nature Biotechnology. (link)

• ProteinGenerator is a diffusion model, based on RoseTTAfold, that can generate both protein sequences and structures. It’s a key step toward optimizing protein functions. bioRxiv. (link)

⚒️ In the Community

Education, resources, and events.

• Have some free time? Like to play around with biology? Join the Homebrew Biology Club Grand Prix. Participants will develop a project over the next few months (whatever you’d like) and can win up to $10,000 at a year-end showcase. Email me if you want feedback or help with your ideas.

• The Underground Garden Club released a DIY biology curriculum that covers everything from building a smartphone-based fluorescence microscope to making jet fuel with microbes.

• Have you tried Mojo Lang (apparently up to 35,000 times faster than Python) in your research? I’d love to hear about it. Drop me a line!

📺 Meme of the Week

“Please laugh.”

“It's not Nature Nature but it's from the Nature publishing group" (@OdedRechavi)

See you next week! In the meantime, find me on Twitter or LinkedIn.

— Niko McCarty

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

Tap tap tap.

Today, we’ve got news about AI mind readers, a child who underwent brain surgery while in the womb, and (another) problem with lab-grown meat. Scroll to the end for a beautiful chart about the Anthropocene & some details on insect engineering companies. Fun.

Also. news items are now sent on Thursdays. Research roundups are sent on Sundays. Essays in-between (sometimes).

Let’s dive in.

🔥 Picks of the Week

News highlights in 3 minutes.

1/ The Problem with Lab-Grown Meat

Back in April, a little-known paper appeared on the bioRxiv preprint server and proclaimed from the mountain top: “Hear ye, hear ye, those of you who spend restless nights dwelling upon the inefficiencies and cruelties of our modern agricultural system. I bring bad tidings! Cultured meat, grown in the lab, could release between 4 and 25-times more emissions than the global beef industry! If it ever scales commercially, anyway.”

The proclamation is troubling; the preprint even more-so. It suggests that each kilogram of lab-grown meat would produce somewhere between 246 and 1,508 kilograms of carbon dioxide emissions (a wide estimate, I know) with current technologies. This will fall over time.

But even before this preprint, it was unclear whether cultivated meat would ever be produced cheaply enough, and at a high enough scale, to compete with the normal stuff. Consider the cost: You need to “feed” the cells with protein building blocks, and amino acids alone account for $7 to $8 per pound of cultivated meat, according to some experts.

Or consider the scale: We need to grow these cells in massive bioreactors (and keep them completely sterile). But where are these bioreactors going to come from? The waiting list to rent out a large bioreactor, last I heard, was something like 4 years.

Despite the trouble, there is hope. The first lab-grown burger was made for $330,000 back in 2013. Now, it costs about $9. I agree that cultivated meat is a bet worth taking, because we’ll learn a lot, even if it fails. Consider it our moonshot for food.

Read more in IFL Science & Asterisk Magazine

2/ Little Cloned Horse

Wild Mongolian horses, called takhi, once roamed the mighty Asian steppes. There are just 1,900 left today, and “nearly all of them are descended from just 12 animals captured from native habitats between 1910 and 1960,” according to reporting by Emily Mullin in WIRED.

A company called ViaGen has now cloned these horses (and they’ll do the same for your dog for about $50k). Seven embryos, made from skin cells collected from a museum-preserved stallion, were implanted into 7 mares. Three miscarried, but the other four advanced into the first trimester. In February, the second cloned takhi was born.

“The scientists behind the effort say this second birth is evidence that cloning could be a viable strategy for saving endangered species.” Just don’t hold your breath for woolly mammoths!

Read more in WIRED.

3/ A Vaccine for RSV

A vaccine called Arexvy, and marketed by GlaxoSmithKline, has been approved by the FDA for adults aged 60 and older. It is used to prevent respiratory syncytial virus, or RSV, which causes about 60,000 hospitalizations in this age group each year.

The vaccine was 82.6 percent effective in preventing lower respiratory tract illness this age group in a randomized, controlled trial with 250,000 participants. Those data were published in The New England Journal of Medicine in February. The vaccine also reduced the risk of developing severe RSV infections by 94.1 percent.

Scientists have been trying to make a vaccine against RSV since the 1960s, and this is the first success story. There’s a nice account of that history in Nature.

Read more in The New York Times & Ars Technica

4/ AI: Mind Reader

If you stick some people in an fMRI machine, and have them listen to a podcast, you can use AI to decode some of the words and phrases that they are hearing. Non-invasive brain decoding! Now everyone can hear me obsessing over whether or not I turned off the oven!

For a recent study in Nature Neuroscience, researchers first trained an AI model (GPT-1 from OpenAI) on:

• English sentences scraped from Reddit,

• 240 stories from TheMoth Radio Hour,

• and transcriptions from the Modern Love podcast.

Then, three participants visited a laboratory in Austin, Texas and spent 16 hours over several days listening to the podcasts while in an fMRI scanner, according to reporting in The New York Times. “The researchers then used a large language model to match patterns in the brain activity to the words and phrases that the participants had heard.”

The model worked even when people listened to new podcast episodes; those that weren’t part of the training data. In one instance, “a user heard the words ‘I don’t have my driver’s license yet.’ The decoder returned the sentence ‘She has not even started to learn to drive yet,’” according to reporting in MIT Technology Review.

When a person “resisted” listening by counting to sevens, or by naming different animals, the AI model’s accuracy plummeted. In the future, maybe the best way to defend our thoughts will be to think about dogs.

(This paper was submitted to the journal more than a year ago, in April 2022. What might be possible today?)

Read more in MIT Technology Review & The New York Times

📤 In the News

Other quick-hit news items you might have missed.

• Eli Lilly’s Alzheimer’s drug, donanemab, slowed mental decline by 35% for a fraction of the 1,736 people who enrolled in a clinical trial. But full results have not yet been published. Remember that “the press release is all any of us have to go on, which means that we are surely looking at the most optimistic take possible,” writes Derek Lowe. (link)

• A child successfully underwent brain surgery — while in the womb! — and is now 7 weeks old. (link)

• Of the 22 people on Neuralink’s animal research oversight board, 19 were employees of the company, according to reporting in Reuters. (link)

• A more representative human genome sequence, based on DNA from 47 ethnically diverse people, was published yesterday. (link)

• After growing yeast for 3,000 generations, the organisms clump together and change “from a soft, squishy substance to something with the toughness of wood.” The dawn of multicellularity was…wood? (link)

• “Less than five” children in the U.K. have been born using mitochondrial replacement, in which a mother’s defective mitochondria are replaced with healthy ones from a donor. Also referred to as three-person in vitro fertilization. The first “three-person IVF” happened in the U.S. in 2016. (link)

• Moderna made $680 million more than expected in the first quarter of 2023, but the company still intends to hike its COVID-19 vaccine price by 400%. (link)

• Emily Whitehead was the first child to receive a CAR-T cell therapy. It cured her of cancer nearly 11 years ago, and she graduates from high school in two weeks. (link)

• The top private raises in biotech from April; Orbital Therapeutics tops the list at $270M. A woman’s health company, called Antiva Biosciences, also made the list at $53M (they’re making therapies to treat HPV infections.) (link)

• This is interesting; Genemod just raised $4.5M in seed funding to make, basically, a high-powered electronic lab notebook that tracks everything “from data acquisition and project documentation to inventory management and reporting.” (link)

• Lots of scientists are talking about how CRISPR-based gene therapies will be too expensive (an estimated $2M for Vertex’s sickle-cell disease treatment), but few are actually proposing solutions. (link)

🧠 Musings

Fun stuff that has little to do with biotech.

• Romans lost a lot of jewelry in their bathhouses. People 2,000 years ago == people today. (link)

• We finally figured out how smell receptors, in our noses, capture scent molecules in the air. Beautiful stuff. (link)

• Theodor Diener, the first person to discover viroids (an infectious agent that is 1/80th the size of a typical virus) has died at 102. (link)

• Da Vinci’s notebooks are blotched with black stains. Now we know why: Mercury sulphide in the protective paper. (link)

• Those who are “awed” more often “are kinder, more environmentally friendly, and better connected to others.” Another excuse to read this newsletter? (link)

• Italian scientists made a fully rechargeable battery using entirely edible components. Most of the batteries used in ingestible cameras (like for colonoscopies) are super toxic. Perhaps this could replace those someday. (link)

• A perusal of 5,000 papers suggests that up to 24% (in medicine) could be “made up or plagiarized.” Prior studies had suggested 2%. The real number is probably somewhere in-between. (link)

• OpenAI is building a tool to identify which parts of an LLM are responsible for a given behavior. They’re staring with GPT-2. The code is currently open-sourced on GitHub. (link)

• The U.S. is running out of monkeys for biomedical research. (link)

📈 Data Brief

One chart about biology and our world.

Abundance vs. Biomass

There are an estimated one ninillion bacteria on planet Earth. Or, put another way, there are one billion microbes on Earth for every star in the observable Universe.

But the biomass of bacteria is relatively small — about 100 billion metric tons in total. There are far fewer trees, but their total mass is much greater — about 450 billion metric tons. Plants alone account for 80 percent of all biomass on Earth. This planet is so beautiful, and so diverse. But now, most of it is concrete (4,000 pounds are made each year for every man, woman, and child.)

⚒️ Note of the Week

On companies and underrated ideas.

Lately, I’ve been thinking a lot about how gene-editing gets used in the real world. An application that I’ve heard very little about is engineered mosquitoes, and how they can be used to curb diseases. I’m familiar with Oxitec, sure, but they’re really just a big fish in a small pond. There are many other up-and-coming insect engineering startups. Here are a few:

Algenex is using engineered insects to mass-produce proteins (and Ynsect uses mealworms to do the same.) Synvect has made a CRISPR-based tool to control insect populations, be they mosquitoes or flies or anything else. Their technology has already been licensed to Agragene, a pest control company specializing in agriculture. (FMC is another company that specializes in killing off insects that damage crops, but they do it by spraying pheromones on the plants.) Entocycle makes insect farms. Protix and Hexafly use insects to make food ingredients.

See you next week! In the meantime, find me on Twitter or LinkedIn.

— Niko McCarty

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

A massive mosquito factory is under construction in Brazil, according to a recent article in Nature. My initial reaction — huh? — quickly gave way to intrigue, which soon morphed into confusion. Many folks have already commented on the news, but nobody has said this: This mosquito factory will be outdated as soon as it’s completed.

The factory will produce up to five billion mosquitoes each year, each of which will be infected with a bacterium, called Wolbachia. These infected mosquitoes (all Aedes aegypti) will be released in cities across Brazil; they’ll breed with their wild counterparts and pass the microbe to their offspring. Mosquitoes infected with Wolbachia have a reduced ability to transmit viruses to people. Cases of dengue and Zika will slowly fall. 

At least, that’s the goal.

The World Mosquito Program (tagline: “Releasing Hope”) is behind the Brazil factory. They’ve already carried out controlled releases of Wolbachia mosquitoes in Indonesia and Rio de Janeiro. Those trials showed a 77 percent and 38 percent drop in dengue cases, respectively, but similar projects have failed elsewhere. During trials on a Vietnamese island, Wolbachia mosquitoes were released and then entirely vanished for reasons that we still don’t fully understand.

Still, any drop in dengue is a success. Mosquitoes kill something like 700,000 people each year. In just the last five years, 481 municipalities in Brazil “detected community dengue transmission for the first time, accounting for 8.7 million new individuals at risk,” according to a recent study.

Despite the World Mosquito Program’s mixed success, the Wolbachia approach is flawed for many reasons: Its effectiveness varies widely from one climate to the next; released female mosquitoes still bite people; and Wolbachia can possibly spread to other types of insects and harm their populations. We have better ways to control mosquito-borne diseases, but only if we embrace gene-editing.

To understand these “better ways,” though, we first have to understand how workers at the Brazil factory will breed and release mosquitoes, and why it’s problematic. The World Mosquito Program (which is partially funded by the Gates Foundation) already operates a smaller factory in Medellín, Colombia that makes about 30 million mosquitoes each week.

It works like this: First, you take a bunch of mosquito eggs and infect them with Wolbachia. After a few weeks, you take the infected females, throw ‘em in a cage (with the temperature set to at least 27 degrees Celsius, and humidity at more than 75 percent), and let them mate with uninfected males. If you’re strapped for cash and don’t want to build a custom sweat box, there’s an easier way: Take a small electric light bulb, place it in the cage, and then drape a wet towel over it. (Good enough!)

Mosquitoes can survive on little more than live rodents (or just bags of blood donated by a slaughterhouse) and sugar water. After two days of mating, the females lay about 200 eggs each. Larvae hatch in 6-12 hours and can reproduce within 7 days. It’s theoretically possible to make about 10 billion mosquitoes from a starting batch of 100 females in as little as two months.

Once the mosquito factory has made all these insects, they are packaged into boxes or cups and then released in “strategic” areas within a city, like near swampy water or in dengue-ridden neighborhoods.

Now for the catch: The Wolbachia approach is flawed because females (the only sex that actually bites and transmits the microbe) are released along with the males. Many of them will bite people. The infected insects also vary massively in their fitness levels; some of them are quite healthy, while others aren’t strong enough to breed in the wild. Of the five billion insects the new factory releases yearly, only a fraction will actually “do their job.”

A new method called the precision-guided sterile insect technique (pgSIT), solves many of these problems. To use it, mosquitoes are bred in exactly the same way that I’ve already described, but with one major difference: Instead of infecting females with a bacterium, they are genetically engineered to express the Cas9 protein (one part of the CRISPR system), while male mosquitoes are engineered to express guide RNAs. 

When the insects mate, their offspring inherit both the Cas9 and the guide RNAs. These molecules come together, stick to mosquito genes, and cleave them in two. The broken genes don’t work anymore.

Here’s the clever bit: The guide RNAs are specially designed to target two genes in particular; one for female survival and another for male fertility. When a gene-edited female lays her eggs, then, the female offspring never hatch, while the males hatch but cannot produce offspring of their own. (In males, the guide RNAs chop up a gene called beta-tubulin, which is required for sperm to swim.)

In other words, pGSIT makes it possible to eliminate biting females and render males sterile in one fell swoop, without adding any time to the normal mosquito breeding program. This technology isn’t a gene drive; the CRISPR components don’t pass from one generation to the next, because only the males survive, and the males can’t make children.

It has other advantages, too. CRISPR works in just about every living thing on the planet, so pgSIT can be used in many different insects, including Aedes aegypti (which spreads dengue and Zika), Anopheles gambiae (which spreads malaria) and Drosophila suzukii (a pest that lays its eggs in peaches, strawberries, and grapes.) The Wolbachia method is not as versatile.

Now, I’m not gonna sit here and try to convince you that this method is perfect. Nothing ever is. The method hasn’t even been tested in the real world as far as I know, and experiments in the lab suggest that you’d have to release a lot of these mosquitoes (perhaps 10 gene-edited mosquitos for every one in the wild) to make a sizable impact. But the technology has already been licensed to a crop pest control company, called AgraGene, and initial experiments in the lab seem promising.

Still, it will be difficult (but certainly not impossible) for the technology to earn regulatory approval, because gene-edited mosquitoes sound like a plot point in a sci-fi horror movie.

Oxitec, a British company that uses a similar technology to control mosquitoes, has already released their transgenic insects in the Florida Keys, Brazil, and elsewhere. But it took years for them to get EPA approval, because nobody in government had any idea who should regulate this niche technology. Oxitec’s technique works really well, though: In dengue-prone neighborhoods in Brazil, it caused a 96% reduction in the mosquito population. (The company’s technology does not rely upon CRISPR-Cas9 but does require that mosquitoes be fed a specific antibiotic during breeding. This suppresses their immune systems and probably makes them less fit in the wild.)

I can’t predict the future, or tell you what will happen with Brazil’s new mosquito factory. But I do know this: Genetic engineering has endowed us with a radical ability to control our environments. It can be used to decimate insects to a degree that has never been possible in the course of human history. A mosquito may have killed Alexander the Great, but soon, disease-carrying insects could be no more.

Vanquishers will become the vanquished.

Thanks to Nikolay Kandul for helpful discussions.

Note: Only female mosquitoes can transmit Wolbachia to offspring, and this is why the World Mosquito Program releases both sexes. I still think the pgSIT approach would streamline breeding and generally work better.

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

Now let’s get into it!

🔥 Five Amazing Things

(That happened this week…)

1/ CRISPR Protein Penetrates Cells

Not one, but two new papers report a better way to deliver Cas9 or Cas12 gene-editing proteins into living cells. The key is to mix the proteins with cell-penetrating peptides that drag the enzymes into cells. In one study, this new method was used to edit genes in immune cells, harvested from both human and mice, with 98 percent efficiency (which is very good.)

How? Peptide-Assisted Genome Editing (PAGE) has two components: A cell-penetrating Cas9 (made by fusing the gene-editing protein to the TAT protein from HIV) and the peptides. The two are mixed together for 30 minutes, and then everything is incubated with human cells. The protein moves into the cells (no electricity or chemicals needed!) and edits the genes inside. This works for many different cell types, and the method can also be used to deliver several different gene editors at once.

So what? It’s an easier way to get CRISPR into cells! Other methods to deliver Cas9 (like with viruses) are way less efficient, and seem to vary wildly from one cell to the next.

Read more at Nature Biotechnology

(Similar paper at Nature Biomedical Engineering.)

2/ Live Long and Prosper, Lil’ Yeasty Boys

Yeast cells usually live for about one week. But now, their engineered brethren can live about 82 percent longer.

Yeast die for two reasons: Either their nucleolus (where the DNA is kept) degrades and dies, or their mitochondria whimpers out and they stop making energy. If you build a synthetic gene circuit that toggles between these two “age-related states,” back-and-forth, then it takes longer for the yeast to die from either one, and they live much longer.

How? Two important genes control the nucleolus and mitochondrial “aging states”: Sir2 and HAP. In this paper, these genes were connected together into a negative-feedback loop, and then yeast were studied in tiny channels with time-lapse photography. The levels of Sir2 went up and down throughout the yeasts’ lives.

So what? If you just boost levels of Sir2 or HAP, yeast won’t live that much longer. But if you start to play with the times during which these genes are expressed, you can make cells age differently. Often, when we engineer a cell, we only mess with the magnitude of an effect; this study suggests that we should think more about the timing, too.

Read more at Science.

3/ I Swear I’m Not a Robot

Yeah, ChatGPT is cool and all, but can it write my poster abstract? Not yet.

AI-generated abstracts were classified as such 99.98% of the time, according to a new study. And when AI-generated abstracts were shown to “blinded human reviewers,” those reviewers correctly identified the fake ones 68% of the time (but also said that 14% of human-written abstracts were written by an AI. Is this proof that scientists really do write like robots?)

How? Science abstracts were pulled from five different medical journals and then fed into ChatGPT. The AI then generated a bunch more abstracts using similar verbiage. All the abstracts were mixed together and shown to humans, or fed into AI text detection algorithms.

So what? This study sheds light on how, exactly, AI-generated text differs from the real stuff, and how it could be used to (soon) write entire research papers. “ChatGPT writes believable scientific abstracts, though with completely generated data,” according to the study’s authors. The AI tool also created text that was “vaguer and more formulaic.”

Read more at npj Digital Medicine.

4/ Vaccine Printer Go Brrrrrrr

Instead of sticking a needle into someone’s arm, a new paper shows that you can load vaccines into a “microneedle patch” that slowly dissolves and immunizes people just as well (or better) than traditional methods. Also, the patches don’t need to be stored in the fridge, or be administered by a healthcare worker; you just slap it on.

How? Vaccines (basically little fat bubbles filled with mRNA and some dissolvable polymers) were physically printed onto microneedle patches using a robot. These patches can be stored at room temperature for at least 6 months.

So what? I mean, come on. This is a much better way to administer vaccines, if it actually scales up. The vaccine printer can make lots of different types of vaccines, including protein, DNA, and mRNA ones, but I’m sure this is all quite expensive right now. But the printed vaccines are very good!

In one experiment, the microneedle patches were used to deliver a SARS-CoV-2 vaccine into mice, producing immune responses similar to a traditional injection. Printed vaccines caused mice to have a faster immune response.

If these printers were set up in resource-starved countries, where malaria and other diseases are endemic, they could make a world of difference.

Read more at Nature Biotechnology (some coverage in MIT News, too.)

5/ Lots O’ Gene Therapies

Not one, but two applications for sickle-cell gene therapies have been submitted to the F.D.A. If approved, these wouldn’t be the first gene therapies on the market, but they would be the first gene therapies for a disease that affects something like 100,000 Americans. The only cure for sickle-cell disease, right now, is to replace the patient’s abnormal stem cells, in their bone marrow, with healthy cells from a family member. But that comes with some serious risks, and often fails.

How? The latest F.D.A. application is from bluebird bio. The company uses a modified virus to deliver multiple copies of the correct form of the beta-globin gene into a patient’s blood-producing stem cells. A therapy that uses CRISPR gene-editing to treat sickle-cell disease was also submitted by Vertex & CRISPR Therapeutics in early April.

So what? These gene therapies would push genetic engineering to the forefront of the public psyche, and could have knock-on effects in terms of funding and awareness. Many gene therapies come with a massive price tag, though, so they will probably remain out of reach for most patients for a long time.

Read more at Biospace.

🧪 From the Lab

• Tools to engineer plants just keep comin’! Now there’s a new type of protein (well, not really…it’s the third generation) called PrimeRoot editors that are optimized to work in plants. These enzymes can insert “up to 11.1 kilobases” of DNA into a plant genome. (My upcoming essay for Works in Progress will talk about some of this stuff.) Nature Biotechnology. Read

• A CRISPR-based assay can detect microRNAs associated with cancers in about 20 minutes. Nature Biomedical Engineering. Read

  • Another paper that used CRISPR to detect cancer signals in urine was published around the same time in Nature Nanotechnology. Read

• A tiny, battery-free device, implanted beneath the skin of mice, can record neural activity and body temperature at the same time. Nature Biomedical Engineering. Read

• A nanorobotic hand, made out of DNA, has “a palm and four bendable fingers” that can be used to pick up and move “gold nanoparticles…and SARS-CoV-2 virions.” WTF? bioRxiv. Read

  

• A protein with just 28 amino acids can fold around an iron atom and be used to transfer electrons in living cells. This man-made protein is the smallest yet to have a metal binding site. Nature Communications. Read

• It’s possible to design DNA sequences that respond differently to ultraviolet vs. blue light, and can thus be used to build molecular logic gates. JACS. Read

• Stem cells were induced to form insulin-secreting pancreas cells and then transplanted into diabetic mice, where they successfully restored glucose levels. Nature Cell Biology. Read

• Microbes in the wild ‘talk’ to their neighbors by emitting, and sensing, small chemicals. A new paper engineers a communication network between cells using DNA instead. Nature Communications. Read

• A new sequencing method, called CODEC, is up to 1,000-fold more accurate than traditional next-generation sequencing. “CODEC revealed mutation frequencies of 2.72 × 10⁻⁸ in sperm of a 39-year-old individual.” Nature Genetics. Read

• Wanna start a protein therapeutics company? This review is a good place to start. Nature Communications. Read

• This paper explains how synthetic biology is regulated in Europe. I like it because it focuses on specific examples, including an arsenic biosensor that was tested in Nepal and Bangladesh. Synthetic Biology. Read

• Ribosomes are able to build proteins because they contain a strand of RNA that imbues them with their catalytic power. Now, the ribosome’s peptidyl transfer center has been comprehensively mutated and mapped to better understand how it works, and how it can be engineered to make ribosomes build entirely new materials. Science Advances. Read

• Synthetic carboxysomes (which improve CO2 absorption) were engineered into tobacco plants to enhance photosynthesis and potentially boost crop yields. Nature Communications. Read

• A comprehensive map of how genes interact in fruit flies, followed by the prediction of gene functions using a machine learning tool. Cell Systems. Read

• An automated platform to make riboswitches (RNA strands that bind to small molecules and then quickly switch their structure) that can sense specific proteins. This could be very important for building low-cost medical diagnostics in the near future. Nature Communications. Read

💾 Hack Biology (Software 🤝 Cells)

• General language models were used to evolve antibodies that are already used in the clinic. The AI model suggested mutations to the antibody proteins that increased some of their binding strengths to Ebola or SARS-CoV-2 up to 160-fold. Nature Biotechnology. Read

• Prime editing is a really cool gene-editing method that can make small substitutions or deletions in the genome. Now, deep learning models have been trained on data from nearly 339,000 guide RNAs to create DeepPrime, an algorithm that predicts gene-editing outcomes. Cell. Read

• PASSer is an online tool that predicts allosteric sites in proteins, which are where molecules bind to switch a protein ‘on’ or ‘off’. Just download a protein file (from the Protein Data Bank) and upload it to the free web tool! Nucleic Acids Research. Read

• Create, edit, and annotate plasmids (circular loops of DNA) in the browser. Nucleic Acids Research. Read

  • A similar tool was also recently released, but for entire genomes! PLOS Computational Biology. Read

• Another browser-based tool, except this one lets you draw RNA strands much like you would paint on a canvas. “RNAcanvas automatically arranges residues into strictly shaped stems and loops while providing robust interactive editing features, including click-and-drag layout adjustment.” Nucleic Acids Research. Read

• AI tools designed proteins that bind to other proteins, including the SARS-CoV-2 spike. Nature. Read

• Genome sequences from more than 1,000 microbes were collected, and then AlphaFold was used to predict structures for more than 200,000 of their proteins. Nature Communications. Read

📰 News

• Newly unveiled archival letters from Rosalind Franklin suggest that the brilliant King’s x-ray crystallographer “was relaxed” about her data being share with James Watson. “We found no evidence that she felt robbed—and this letter suggests that she did not feel this way.” In other words, Rosalind Franklin was open and honest with her data; a virtue that few scientists possess in our modern, hyper-competitive landscape. Nature. Read (Also see a summary on Twitter by one of the authors.)

• A few months ago, one participant in a clinical trial for a CRISPR-based gene therapy for Duchenne muscular dystrophy suddenly died. New details suggest that the man, 27-year-old Terry Hogan, did not die from CRISPR gene-editing. Jason Mast for STAT. Read

• The reason we have lagers today (apparently) is because yeasts for a white ale and brown beer “mixed in a cellar of the original Munich Hofbräuhaus….sometime between 1602 and 1615.” How did scientists make this ultra-niche, yeasty discovery? Why, by studying the “genetic histories of yeast,” of course. Ann Gibbons for Science. Read

• Elizabeth Holmes, the ousted founder of Theranos, was convicted of fraud and sentenced to 11 years in prison. But she’ll stave off jail time for a bit longer after appealing an earlier denial of bail. Beth Mole for Ars Technica. Read

• The first children conceived using a sperm-injected robot (which is controlled with a PS5 controller) have now been born. Startups are popping up like flies on spoiled meat. Antonio Regalado for MIT Technology Review. Read

• Some Illumina sequencer softwares had a cybersecurity vulnerability that enabled unauthorized users to take over the devices remotely, alter “data on the instrument” or change “genomic data results in the instruments intended for clinical diagnosis.” Whoops. FDA.gov. Read

• If we want the “biorevolution” to be as disruptive as the “Industrial Revolution,” then we will need a “pop-culture moment” that vaults biotechnology to the forefront of society. This is something I think about a lot, and I’m not sure how to make it happen. More memes and jokes in this newsletter might be a start! Cecilia Manduca on Medium. Read

• Remember all the new weight loss drugs, like tirzepatide, that celebrities are going crazy for? Well, more data is out, and people who took the drug for 72 weeks “lost up to 15.7% of body weight.” Read

• A company called Dalan Animal Health is making “a vaccine for honeybees.” Willow Shah-Neville for Labiotech. Read

• Last week, I wrote about how Ghana became the first African country to approve a new, highly effective malaria vaccine. But there are many other vaccines under development, too! Roohi Mariam Peter for Labiotech. Read

• An easier (and cheaper) way to do single-cell RNA sequencing? Derek Lowe for Science. Read

• Soon, companies will want to sequence the microbes in your poop and then recommend diets. Jessica Hamzelou for MIT Technology Review. Read

• The F.D.A. has authorized Biogen to sell their drug, called Qalsody, “for a rare genetic form of the neurological disorder A.L.S.” These treatments typically cost about $150,000 per year. Qalsody targets a mutation in a specific gene that is only “present in about 2 percent of the roughly 6,000 cases of A.L.S. diagnosed in the United States each year.” Rebecca Robbins for The New York Times. Read

🧠 Musings & Memes

• Cyborg Goldfish, anyone? Kate Golembiewski for The New York Times. Read

• Robots learn to play soccer. (They use their hands a lot!) Tuomas Haarnoja on ArXiv. Read

• A nice article from Aatish Bhatia about how A.I. tools, like ChatGPT, learn to “speak.” The New York Times. Read

• When I was a kid, one of my favorite books was about Balto, the sled dog that ran hundreds of miles to deliver diphtheria antitoxin to Nome, Alaska in 1925. Now, DNA sequencing shows that “Balto was just part Siberian husky, and, contrary to popular legend, he was not part wolf.” Jennifer Ouellette for Ars Technica. Read

• A massive ant farm, housing 500,000 leafcutter ants, will be unveiled at the American Museum of Natural History on May 4th. It is truly a work-of-art. Emily Anthes for The New York Times. Read

📈 Companies

• Vedanta Biosciences, a company in Cambridge, MA that uses “bacterial consortia therapeutics” to treat disease, raised $106.5 million. It’s gonna be used for phase 3 trials of a C. difficile therapy. Read

• Orbital Therapeutics, a company in Cambridge, MA that is making RNA therapeutics using lots of automation and machine learning, raised $270 million in a Series A (the largest so far this year.) Read

• Chunk Foods, an Israeli alt-food company, raised $15 million in seed funding last November and is nearing completion of a factory that can produce millions of plant-based steaks each year, at a cost of about $5 each. “The company develops whole cuts of alternative proteins using fermentation technology and food-grade microorganisms to turn soy and wheat into its proteins.” Read

• Adcentrx Therapeutics, a company in San Diego that fuses proteins together to build cancer therapies, raised $38 million in a Series A. Read

• Calico, the Google-backed biotech company in San Francisco that is studying “the biology of aging and healthspan,” has dosed its first patient in a phase I trial for an ultra-rare disease that causes the brain’s white matter to break down over time. Read

• Seres Therapeutics has become just the second company to get F.D.A. approval for a microbiome therapy. Seres’ drug, called Vowst, is a living microbe that treats C. difficile infections. Allison DeAngelis for STAT. Read

• A beauty company just bought out a Boston-based biotech company that uses AI to discover molecules for $76 million. Read

• Boston-based Life Biosciences says that their gene therapy for NAION (a somewhat rare, age-related disease that causes vision loss) restored sight in primates. Read

• Asimov, a Boston-based company that uses software and a large library of genetic parts to design living cells, published a white paper that explains their technology in more detail. (Note: I’m employed by the company and a co-author on the paper.) Read

That’s it for today! See you next week. In the meantime, find me on the imploding nightmare that is Twitter (@NikoMcCarty), where I haven’t posted in like two weeks, and promise not to clutter up your timeline. That’s a win.

— Niko

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

🔥 Five Amazing Things

(That happened this week…)

Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs. By Elizabeth C. Stahl et al. on bioRxiv.

If you want to edit a gene inside of a neuron, what do you do? Most people would take the two CRISPR gene-editing components (a Cas9 protein and guide RNA), package them up inside of a virus, and then inject the viruses into the skulls of mice. These viruses enter the brain and deliver the gene-editing ingredients into neurons. Unfortunately, they can also trigger immune responses, and they are not super efficient at gene-editing some parts of the brain.

A new study from Jennifer Doudna’s lab shows that ribonucleoproteins (basically little balls of Cas9 and guide RNAs, packaged inside a fat bubble) can edit genes in the brain better than viruses. These fat bubbles are injected straight through the skull. In one experiment, they successfully edited 14% of neurons near the injection site, which was sufficient to reduce symptoms in a mouse model of a neurological disorder, called fragile X syndrome.

These ribonucleoproteins also caused a lower immune response compared to the viruses, and are much easier to make in the lab. Delivering a 25μM dose of the Cas9 ribonucleoproteins led to lower levels of vehicle-specific antibodies 90 days post-injection, compared to the viruses, and also did not cause T-cell gene signatures to spike up.

Promising new malaria vaccine for kids approved in Ghana. Associated Press. Read

Ghana is the first country to approve a new malaria vaccine developed at the University of Oxford. This is not the first vaccine approved to prevent malaria, but it is by far the most effective. A clinical trial from Burkina Faso, published last year, showed that this vaccine was up to 80% effective at preventing malaria (compared to an existing vaccine distributed by the WHO, called Mosquirix, which is about 30% effective). The vaccine, called R21/Matrix-M, is made by fusing a protein secreted by the malaria parasite to a hepatitis B surface antigen that helps the vaccine enter cells.

The African nation approved the vaccine for use in children between 5 and 36 months of age. This vaccine is being “scaled up” at the Serum Institute of India, which “says it could produce up to 100 million doses depending on demand.” Malaria currently kills about 500,000 children every year; enough to fill nearly 7,000 school buses. That is a sobering thought.

Tropic’s non-browning gene-edited banana cleared for production in the Philippines. Press release.

In a recent essay, I explained how a U.K. company, called Tropic Biosciences, had developed bananas that stay yellow for more than a month on grocery store shelves. It’s a remarkable achievement, with the potential to save billions of bananas from going to landfill each year. The company estimates that its fruit could reduce carbon emissions across the banana supply chain by 25 percent.

These gene-edited bananas were submitted for regulatory approval in the Philippines (a top five global exporter of bananas) sometime last year. The country has now ruled that the gene-edited bananas are exempt from GMO regulations because they do not carry additional DNA sequences, and so they will not have to pass through strict safety testing. “With this determination the Tropic non-browning can be freely imported and propagated in the Philippines,” according to a company press release.

(Side note: The man who developed the Cavendish banana, the main banana we all eat today, was a Brit named Sir Joseph Paxton. He cultivated the bananas “in state-of-the-art greenhouses he'd designed in Derbyshire for the duke of cavendish.” Thanks to Tom Ellis for sharing.)

Read my essay here.

Targeting Sex Determination to Suppress Mosquito Populations. Ming Li et al. in bioRxiv.

Mosquitoes have killed more humans than any other animal (even sharks, my great nemeses.) They spread Zika, malaria, dengue, and chikungunya. Genetic engineering can be used to eradicate mosquitoes in two ways: Through gene drives or the “sterile insect technique.”

The former is a controversial tool that uses clever bioengineering to propagate lethal genes through a species, thus causing a population to collapse. Gene drives are difficult to control, and none have been tried in the wild. The sterile insect technique, by contrast, has already been used in lots of places. You basically x-ray a bunch of male mosquitoes to make them sterile, and then release them en masse into nature. The males fly around, breed with females, and produce eggs that never hatch. The population plummets. This is the method that Oxitec, a UK company, has been using to curb mosquitoes in the Florida Keys and parts of Brazil.

Unfortunately, the sterile insect technique is tedious and slow. X-rays are horribly inefficient. Some males become sterile, but others don’t. A new study has improved upon this process, using CRISPR gene-editing to make males sterile with very high efficiencies. When sterile males were released into a cage with females at a 20:1 ratio (which is quite a lot), the population went extinct after about five generations. Not all gene-edited males were 100% sterile, but these results may be a more promising means to control mosquitoes in the wild.

Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Everette K.A. et al. in Nature Biomedical Engineering.

Sickle-cell disease is a genetic disorder that affects an estimated 100,000 Americans (and 1-in-365 Black Americans). It is caused by a mutation in the β-globin gene, which leads to abnormally shaped red blood cells that can pool in the spleen and block blood vessels. A normal red blood cell lives for 120 days; sickle cells live for 10-20 days.

Red blood cells are made by stem cells in the bone marrow. A research group at Harvard has now used prime editing — a gene-editing tool that can make small insertions or deletions in the genome — to directly fix the β-globin gene in anywhere from 15 to 41 percent of these stem cells. When the edited stem cells were transplanted back into mice, they engrafted into the bone marrow and produced healthy red blood cells after 17 weeks.

This new tool could be a “one-and-done” cure for sickle-cell disease. Right now, the only FDA-approved treatment is to transplant blood stem cells from a healthy person into a sickle-cell patient, but some people never find a suitable donor. This new paper would solve that problem because no donors are needed — the stem cells come from the patient’s own body.

See this Twitter thread for more details.

This is the future I want: Live in a van and roam the world. Engineer microbes while sitting upon my twin-sized mattress. By putting labs into vans, we could democratize access to biotechnology. We could bring educational lessons to kids in rural areas, and expand the field to borders far outside of Boston and San Francisco.

📎 Papers

• Strands of DNA can be used to build molecular logic gates. This paper shows how to build every type of gate — NAND, NOT, NOR, and so on — using DNA, and even includes an open-source software to design everything. Nature Communications. Read

• This paper presents a new way to get DNA into skeletal muscle by engineering fusogen proteins, which help viruses stick to and enter human cells. Cell. Read

• A suite of calcium sensors, called NEMO, are way brighter than any other proteins currently available to monitor neural activity. These proteins are used to “watch” neurons fire in real-time, in both mammals and plants! Nature Methods. Read

• A new tool to “hypermutate” genes inside living cells, at a rate of roughly 5 mutations every 1,000 bases. Nucleic Acids Research. Read

• Engineered microbes could be used to build biomaterials, and recycle atoms, on the Moon or Mars. This is a beautiful primer to the field of space synthetic biology. Nature Communications. Read

• Every living cell uses DNA as its genetic material, and DNA itself is made up of individual molecules (like A, T, C, and G.) But what happens when cells are engineered so that they can’t make their own DNA, but are instead “fed” the raw molecules? Well, they grow a bit slower, and they look a bit odd, but they still survive. eLife. Read

📰 In the News

• AI will change how biology experiments are done. Most pipetting will become automated. Machines will be programmed with little more than our voices. “It is time now to begin working on what the laboratory of the future will look like: how we can make it as productive as possible, and how we can make sure that it remains safe and controllable in the years to come,” writes Sam Rodriques. Read

• UC Berkeley scientists Jennifer Doudna and Jill Banfield got $70 million in funding to edit microbes, inside cow stomachs, to reduce methane emissions. Fierce Biotech. Read

  • Interestingly, a startup called Native Microbials recently won $1.4 million to do something similar.

• Fertility gets little attention from federal funders. But “a new crop of biotech startups” are pioneering methods to make gametes (sperm or eggs) from stem cells, and to enable same-sex couples to produce biological offspring. The New Yorker. Read

• A few months ago, a study in Nature suggested that synonymous mutations — changes in DNA that do not change the amino acid sequence of a protein — were deleterious. That is, they actively hurt living organisms. The study was debunked recently, and the whole saga offers an intriguing window into just how much a prestigious journal can neuter criticisms. Twitter thread. Read

• A gene therapy for Duchenne muscular dystrophy, developed by a company called Sarepta, is expected to be approved (or rejected) by the F.D.A. by May 29th. The F.D.A. was leaning toward rejecting the gene therapy earlier this year, according to STAT reporting, and then a “top official intervened.” STAT. Read

• Roundworms fed cannabinoids get the munchies, according to a study that was published on 4/20. Ars Technica. Read

• A profile of Tracie Seimon, a scientist who uses DNA sequencing to detect and monitor wild species in “Peru, Myanmar, Vietnam, Cambodia, Russia, Uganda and Rwanda.” Quanta Magazine. Read

🧠 Musings

• For the first time, scientists have read a text authored by Ptolemy, the renowned Roman astronomer and mathematician. Ars Technica. Read

• People say that synthetic biology doesn’t scale. That may be (mostly) true over the last couple decades, but it shouldn’t stop us from imagining entire buildings powered by photosynthetic algae or patio furniture woven from materials produced from yeast. A new review imagines this implausible future. Rachel Armstrong. Read

• An upcoming, week-long hackathon will challenge attendees to build products at the intersection of synthetic biology and games. Sounds interesting and registration is free. Two days are in San Francisco. Read

• This looks like a useful Python tool to analyze genomics data in Jupyter notebooks. Read

📈 Companies

• Microbes sold by Pivot Bio, a company that uses living organisms to replace the nitrogen in synthetic fertilizers, “were used on more than 3 million acre[s] of U.S. cropland in 2022 — 300% year-over-year growth.” Press release. Read

• AI tools can now design never-before-seen proteins. But how do you know whether they’ll work in the real world? A new startup, called Adaptyv Bio, is building a microfluidics platform to build and test lots of proteins at once, using “1,000 times fewer reagents” than any existing alternatives. This is very important. Looks like a cool company. Labiotech.eu. Read

• Moderna is using quantum computers, developed by IBM, to design future therapeutics. Fierce Biotech. Read

• Cultivarium, a company building molecular tools for non-model organisms (think everything but E. coli and yeast), signed an agreement with the nonprofit, ATCC, to help get their microbes to researchers. This could be an important step toward democratizing access to extremophiles and other cool bugs. Press release. Read

• Complement Therapeutics, a company building gene therapies for vision-related diseases, raised €72 million in Series A funding. Press release. Read

• Eli Lilly is adding 200 jobs at its drug manufacturing plants in Indiana, which will cost $3.7 billion together. Press release. Read

Thanks for reading,

— Niko McCarty

Email | Twitter | LinkedIn

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.

At 8 o’clock on a February morning, Eli Black smashed a hole in a window on the 44th floor of New York City’s MetLife building and jumped.

It was 1975, and the chairman of United Brands was responsible for a sizable fraction of the world’s banana trade. An associate later told The New York Times that Black was “under great strain because of business pressures.”

Those pressures were not related to irksome employees or dwindling revenues. The problem was, rather, that Black had planned to bribe Honduran officials in exchange for favorable tax rates on banana exports, and the U.S. government found out about it. 

Honduras was set to impose a slight tax hike on 40-pound banana crates, which would have cost United Brands (then the largest shareholder in the United Fruit Company, now Chiquita) some $7.5 million per year. A lawsuit alleged that Black’s company had failed “to disclose substantial payments to officials of foreign governments in order to secure favorable treatment.” In 1978, the company pleaded guilty to conspiring to pay $2.5 million to a Honduran economic minister. (In 1954, the C.I.A. deposed a democratically-elected government in Guatemala at the behest of the same company.)

Just a few decades ago, the greatest threats to bananas were political maneuverings and military coups. Today, the greatest threats are biological: Fungi that wipe out fields, and spoiled fruits that slash into razor-thin margins. To combat these threats, genetic engineers are making bananas that fend off fungi or ripen slower than natural varieties. Their work could save five billion bananas from being thrown in the trash each year in the United States alone. 

A British company, called Tropic Biosciences, raised $35 million last year to make gene-edited bananas that don’t brown like a normal fruit. But questions abound: How long do “non-browning” bananas really last? Is banana spoilage an actual problem? And will these bananas — designed for a hungry planet that seems to prize “naturalness” over everything else — even make it to the dinner table?

The Death of Gros Michel

There are over 1,000 types of bananas in the world, but men live and die for the Cavendish, a staple crop for 40 percent of people. The Cavendish makes up about half of all bananas grown on Earth, but accounts for 99 percent of exports. 

Our modern reliance on the Cavendish only happened because of a historical accident. Until the 1950s, the Gros Michel was the main banana export. It had sweet flesh and thick skin, which made it easy to ship. (Every time you eat banana-flavored candy — like a Laffy Taffy or Runts — you are tasting an artificial flavor based upon the Gros Michel). By 1965, though, these bananas nearly vanished from Latin America.

The Gros Michel trees were destroyed by a fungus, called Fusarium oxysporum Tropical Race 1, which clings to boots and survives in soil for many years. It invades plants through their roots, spreads through the xylem, and turns the leaves yellow. Dying trees smell like rotten flesh.

As banana plantations collapsed, Dole and Chiquita switched over to the Cavendish, mainly because of its natural resistance to Tropical Race 1. Evolution cannot be defeated for long, though, and a new type of fungus has now arrived. In 2013, a Fusarium fungus — called Tropical Race 4 — was identified in Mozambique. From there, it “travelled to Lebanon, Israel, India, Jordan, Oman, Pakistan and Australia,” according to an article in WIRED. “In 2018, it was found in Myanmar.” This new fungus now threatens the Cavendish banana, and scientists worry that it may already be in Latin America. The race is on to make a resistant Cavendish using gene-editing tools. 

A group of Australians were the first to make that happen; in 2017, they took a single gene from a nematode, pasted it into the genome of a Cavendish tree, and showed that the gene-edited plants were completely resistant to the fungi.

Gene-edited bananas are not yet being grown commercially, to my knowledge, but a Dole plantation in Central America is starting field trials for a disease-resistant variety that was developed by Elo Life Systems, an American company. Kenya, Malawi, and Uganda are also gearing up for gene-edited banana trials. 

Money is also pouring into the field, fast. The Gates Foundation gave $7.6 million to Australian scientists to make Cavendish bananas enriched in vitamin A for cultivation in Uganda (where about 9 percent of people are vitamin A deficient). And two Israeli companies — called Evogene and Rahan Meristem — teamed up to make gene-edited bananas that are resistant to another disease, called Black Sigatoka, which is caused by a different type of fungus.

There is clearly a need for gene-edited bananas, and we have the technology to make them a reality. But crafting bananas that don’t go brown, and then growing them at scale, will prove a greater challenge.

Be Still, My Spoiled Fruits

The U.S. eats something like 7 billion pounds of bananas every year. Most are imported from Costa Rica, Guatemala, and Ecuador. After a banana is picked from the tree, it is stocked on grocery store shelves within two weeks. The fruits are shipped on large container vessels; tightly packed in refrigerated crates so that they don’t ripen during transit. When the bananas arrive at a port, the crates are filled with ethene gas to initiate ripening. A single overripe banana in a large crate “can cause a chain reaction that may wreck as much as 15 percent of a shipment.”

Of all the bananas shipped to the United States, we throw away about 5 billion of them. This fruit is discarded more than any other food in grocery stores, according to a 2018 study from Sweden. This may not seem like a big deal (bananas naturally decompose into fertilizer!), but it means that we waste a lot of water and burn a lot of diesel to grow and ship bananas that people don’t end up eating.

It takes 1.28 kilograms of CO₂ and 330 liters of water to make one kilogram of bananas, according to a 2015 study from Ecuador. This, ultimately, is the reason why Tropic Biosciences and other companies are trying to make bananas that don’t ripen so quickly: The economic impacts could be massive.

They are also fortunate, in part, because scientists have been studying bananas, and why they ripen, for more than fifty years. Most fruits brown when you pinch them because an enzyme, called polyphenol oxidase, turns phenols into quinones, which then react with other molecules to make melanin, a dark pigment. Polyphenol oxidase is produced in banana cells very early during development, and then its levels decline once ripening starts. 

But this is not the whole story. When bananas are ready to ripen, they begin to produce ethene gas, a plant hormone. This gas is produced by an enzyme that is encoded by a gene, called MA-AC01. This gene is regulated, in turn, by a small arsenal of other proteins from the MaMADS family. (Yes, I know. Biology is a chaotic mess!)

These are the basics of how bananas ripen. Now, how do we make them stop?

Haya Friedman, an Israeli biologist, is probably the world’s foremost expert on this niche subject. In 2016, her team demonstrated that, by adding short snippets of DNA or RNA — which can target and “shut down” the MaMADS regulatory proteins — to bananas, it is possible to slow their ripening. (The idea came from tomatoes, which ripen in much the same way.) Friedman’s engineered bananas stay yellow for more than a month after being plucked from a tree.

Tropic Biosciences, the UK company, is undoubtedly familiar with Friedman’s work, because they are using a similar method to make their own gene-edited bananas. Their approach, however, is a clever improvement over everything that came before.

Regulatory Loopholes

We know what happens to bananas when they ripen, and scientists like Friedman have shown how we might slow down this process. But there is just one problem with all this: If you add any genetic material to a banana, the fruit will be regulated as a GMO in many countries, and would then have to pass through intense safety and field trials. Companies obviously want to avoid this, and Tropic Biosciences figured out how:

Every living thing (even bananas!) has a genome made of DNA. Most of this genetic material codes for proteins: DNA is transcribed into RNA, which is then translated into proteins. A significant portion of the genome, though, does not encode proteins. These “other” bits of DNA are called non-coding regions, and some of them make non-coding RNAs.

Now, these non-coding RNAs float around the cell and occasionally match up with a messenger RNA. When the two strands bind together, the messenger RNA is “blocked” from being translated into a protein.

Tropic Biosciences’ gene-editing technology harnesses these non-coding RNAs in a really clever way. Instead of altering a protein-coding gene directly, the company changes the sequences of non-coding RNAs to redirect them to a new protein target. A non-coding RNA that normally blocks Protein X, for example, could be altered to shut down MaMADS proteins instead.

This technology is incredibly intriguing. Since the company does not add DNA to the genome, or alter any protein-coding genes, their plants are not regulated as GMOs in the United States, Canada, Japan, Argentina, or a dozen other countries.

Another advantage: There are many non-coding RNAs that are only expressed in specific parts of a plant, such as the leaves, fruit, or roots. Tropic’s technology can be used to alter non-coding RNAs that are only present in the banana fruit, while leaving the rest of the tree relatively unchanged.

This technology is already being used to make low-caffeine coffee and rice with higher yields, and it has been licensed to an animal engineering company that is making chickens resistant to Avian flu.

Yellow Splendor

Genetic engineering is the only technology that can make the “perfect” banana for our Anthropocene future. But it is not a panacea for our troubles.

Companies are making bananas that ripen slowly or fend off fungi because those are the only things we’ve been studying for decades upon decades. We still don’t know how most genes in bananas work, though, so don’t expect scientists to make jumbo bananas or other “super fruits” any time soon.

There’s also no way to know whether these gene-edited bananas will be commercially adopted. The banana business is dominated by Chiquita, Dole, and Del Monte, which together own most of the banana plantations in Ecuador and Costa Rica. Chiquita alone controls about one-third of the entire banana export market. If Tropic wants to make an actual impact on carbon emissions, they will need buy-in from one of these companies. (As far as I know, Tropic’s gene-edited bananas are not yet being cultivated.)

Despite these concerns, the future of gene-edited bananas is promising. The regulatory tide is shifting.

The Philippines recently revamped their biotechnology policies for gene-edited crops; non-browning bananas were the first application submitted for consideration under the new rules. If the Philippines (a top five global banana exporter) rules that Tropic’s bananas are not GMO, then the company will be able to cultivate fruits on the island. Ecuador and Colombia regulate gene-edited crops that do not carry DNA from another species in much the same way as a normal plant. 

In the United States, there is also a track record of lenient gene-editing regulations, including for foods that are engineered to ripen more slowly. 

In 2016, the U.S. Department of Agriculture decided not to regulate a gene-edited mushroom that browns more slowly, and ruled that they “can be cultivated and sold” in the United States without federal oversight. In May 2021, Tropic also applied for — and later received — an exemption for a non-browning potato developed with their gene-silencing technology.

These gene-edited mushrooms can stay on shelves longer than normal mushrooms and don’t have to be handled as delicately during shipments. They’re expected to reach grocery stores in the U.K. as early as this year.

Now, if you have made it this far in my little essay about bananas and gene-editing, and you happen to be looking for your purpose in life, then let me say this: Look to biology, and plants in particular. Gene-edited crops are a great way to leave a lasting impact on the world. We are entering a renaissance in gene-editing technologies that perfectly coincides with a tidal shift in biotechnology regulations. We are now approaching the Second Green Revolution, and there is room for you here.

And consider this: A small company in the U.K. has made a handful of changes to a banana’s DNA and, in the process, made them last twice as long on grocery store shelves. These bananas could save millions of gallons of water (and billions of fruits) from going to waste each year. The company estimates that their “bananas could reduce food waste and CO₂ equivalent emissions along the supply chain by over 25%,” which “could support an annual reduction in CO₂ emissions of over 9 million tonnes in the banana export market alone.” By engineering plants, in other words, it is possible to achieve so much with so little.

Alas, gene-editing is not a panacea for the world’s woes. In fifty years, some new fungus will emerge that even an engineered Cavendish banana cannot withstand. Biology will continue to adapt and evolve; it will always win the arms race against our human designs. But when the next threat emerges, I will not look to the politicians or Eli Blacks of the world to quash my fears and devise solutions. My head will turn to the biologists — to you. ◼️

Share

Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.