Codon: Biology's Promise

We’ve made incredible strides in health, medicine, and food over the last fifty years. Many of our greatest leaps were borne by biotechnology.

This is from Codon, a weekly newsletter about the bio + tech advances and ideas enabling a brighter future for humanity. Subscribe.


People today are living longer, healthier lives than at any other time in human history. In the early 1900s, influenza killed about 4 percent of people. Today, that number is less than 0.1% in almost every country. Many flu vaccines are made from genetically-engineered cells.

In 1981, more than 23,000 animals were slaughtered to make one pound of insulin, enough to help 750 people with diabetes for just one year. Today, insulin is produced by genetically-altered microbes.

Genetic engineering has been used to create FDA-approved salmon that grow twice as fast as wild species. CRISPR-edited beef cattle with slick coats — which help the animals cope with hotter temperatures — were approved by the FDA earlier this year; the added trait could reduce the suffering of tens of millions of animals each year.

Heme proteins, manufactured by engineered yeasts, help make Impossible Burgers taste like the real thing. And engineered microbes, living in soil, are fixing nitrogen for crops and reducing our planet’s reliance on artificial fertilizers.

In hospitals, state-of-the-art cancer immunotherapies help 9 out of 10 people with treatment-resistant lymphoblastic leukemia experience remission. In factories, microbes turn dirty emissions into acetone, isopropanol, and other chemicals. The whole process is carbon-negative.

All this to say: We’ve made incredible strides in health, medicine, and food over the last fifty years. Many of our greatest leaps were borne by biotechnology.

The next milestones in biology’s story will not be achieved in isolation — they will come hand-in-hand with other fields, like artificial intelligence, automation, and the ‘science of science.’

I’ve devoted more than five hours of my life to this newsletter nearly every weekend over the last two years because I want to capture this story and share it with the world. My hope is that my words will accelerate progress by calling more scientists, thinkers, and builders to action. And for another reason: There’s a serious lack of critical, comprehensive writing about biotechnology and its potential for humanity.

In physics and technology, writers blossom and take center stage in public discussions. They explain the latest NASA mission or iPhone camera to their legions of readers and viewers every week. And I never quite understood why biology didn’t have the same appeal, the same mass adoration from an audience of millions.

But I think I understand now.

Modern physics has achieved visceral and visual milestones throughout the 20th and 21st centuries. Rockets ignite and burn through the atmosphere nearly every week. Breathtaking images of black holes go viral on the internet. We see these images and contend with our own realities; with the meaning of life and our tiny place in the universe.

Technology is much the same. There’s no shortage of writers to marvel at the engineering behind Samsung’s latest curved TV. And these writers, too, have an advantage: The things they write about are right there. You can see the latest big-screen TV, marvel at its size, and reflect on the blocky Panasonic that you grew up with in the ‘90s.

Biotechnology, I’d argue, is both more interesting and more immediately useful to humanity than either physics or electrical engineering. Yet our writing about biology and its potential — even after COVID and a global pandemic — is hamstrung.

Biology doesn’t have many visual achievements. Its greatest feats are slow burns: Smallpox eradicated, access to insulin, and vaccines to defend against a global virus. Scientists work with little cells, invisible to the naked eye. And yet, the fruits of their achievements are all around us, slowly helping humanity adapt to this changing planet. Biology is urgently important because it feeds and heals the world. It will be an essential weapon in our fight against climate change, pollution, and mass extinctions.

Although many journalists write about that shiny, new company that just raised $10 million, few stick around to see whether they actually execute on promises. Fewer still put the large trends — the roadblocks, obstacles, and human triumphs — into context.

Despite the necessity of biotechnology, our coverage of its progress is arguably failing. More than half of U.S. adults believe that “GM foods are worse for health than non-GM foods.” And 49% of adults are opposed to the use of gene editing to reduce their child’s risk for a serious disease.

Neither of these survey results are good or bad. They just suggest that America is divided over biotechnology and how we should use it.

The world will only care about bio-based products when they enter the consumer market and demonstrate clear advantages over existing norms. The world is already sustained by bioengineered foods and medicines, and yet both are industries with hidden walls and obscured views. Most people do not know where their food comes from. Most people take medicines without understanding how they were made.

This newsletter, then, aims to bring biological beauty to the world. The goal is to inspire more scientists to spin-out companies, bring their inventions into the real world, and tangibly solve the world’s biggest problems.

Each week, I’ll continue to round up and comment on new papers from the front lines of the biological revolution. The goal of “The List” is to orient you; to help put research achievements and our rapid pace of progress in a kind of ‘rapid-fire context.’ I’ve expanded the papers to include achievements in robotics, automation, environmental remediation, and other topics. I’m excited by these areas and hope you will be, too. Regular essays will reveal the trends and insights that are expanding humanity’s horizons; they’ll be evidence-based, data-rich, and deliberately deep. The goal is to provide details and context about bio + tech advances that modern newsrooms cannot.

In the meantime, I hope you enjoy this new phase of the newsletter. I’m excited to be on this journey with you.


The List 🔻

Notable science from the last week.

Basic Research
How synonymous mutations alter enzyme structure and function over long timescales. Jiang Y et al. in Nature Chemistry. Link

🔺Mutations in DNA do not always change the amino acids encoded in a protein. But so-called synonymous mutations can still diminish a protein’s overall activity after it folds.

Principles of gene regulation quantitatively connect DNA to RNA and proteins in bacteria. Balakrishnan R et al. in Science. Link

🔺The abundance of mRNAs and proteins were measured for more than 1,500 genes in E. coli under various conditions, thus providing a benchmark for future designs of genetic circuits with predictable outputs. But the scientists make some assumptions that may not hold up to scrutiny.

Dependence of diffusion in Escherichia coli cytoplasm on protein size, environmental conditions and cell growth. Bellotto N et al. in eLife. Link

🔺Molecules move through cells at different rates. Their speeds can be controlled by changing temperature or by bathing the cells in antibiotics.

Generation of transgenic mice expressing a FRET biosensor, SMART, that responds to necroptosis. Murai S et al. in Communications Biology. Link

🔺A genetically-engineered animal helps scientists study where cells are dying, which may be useful to study certain diseases.

Biomanufacturing
Plastic futures and their CO2 emissions. Stegmann P et al. in Nature. Link

🔺Carbon emissions from plastics could be negative by the year 2100, provided that the U.S. swiftly improves recycling and implements more biomass-based production.

↑Point-of-care peptide hormone production enabled by cell-free protein synthesis. DeWinter MA et al. in bioRxiv. Link

🔺Peptide hormones, an important type of medicine used to treat diabetes and other conditions, can be produced in low-resource settings by adding water and DNA to freeze-dried cell guts.

↑Synthetic anaplerotic modules for the direct synthesis of complex molecules from CO2. Diehl C et al. in Nature Chemical Biology. Link

Metabolic engineering of Pseudomonas putida KT2440 for medium-chain-length fatty alcohol and ester production from fatty acids. Lu C et al. in Metabolic Engineering. Link

Low resource integrated platform for production and analysis of capped mRNA. Nwokeoji AO et al. in ACS Synthetic Biology. Link

Efficient co-production of EPA and DHA by Schizochytrium sp. via regulation of the polyketide synthase pathway. Ma W et al. in Communications Biology. Link

Brain

Acute head-fixed recordings in awake mice with multiple Neuropixels probes. Durand et al. in Nature Protocols. Link

Optogenetic activation of visual thalamus generates artificial visual percepts. Wang J et al. in bioRxiv. Link

🔺Progress in creating ‘artificial vision’ using light-sensitive proteins and targeted gene therapy.

↑Engineered retrovirus-like Arc extracellular vesicles for the in vivo targeted delivery of mRNA into the brain. Gu W et al. in bioRxiv. Link

Rattractor - Instant guidance of a rat into a virtual cage using a deep brain stimulation. Sudo N et al. in bioRxiv. Link

🔺Deep brain stimulations control a rat and confine it to a ‘virtual’ cage for up to two weeks.

Computational Tools

Competition-level code generation with AlphaCode. Li Y et al. in Science. Link

🔺Code generated by an AI, called AlphaCode, outperforms 54.3% of human programmers in online competitions.

High-throughput primer design by scoring in piecewise logistic model for multiple polymerase chain reaction variants. Zeng H et al. in Scientific Reports. Link

🔺A new tool automatically generates primers for PCR, all of which are effective in experiments.

A multilevel generative framework with hierarchical self-contrasting for bias control and transparency in structure-based ligand design. Chan L et al. in Nature Machine Intelligence. Link

Decoding CAR T cell phenotype using combinatorial signaling motif libraries and machine learning. Daniels KG et al. in Science. Link

Detecting multiple retinal diseases in ultra-widefield fundus imaging and data-driven identification of informative regions with deep learning. Engelmann J et al. in Nature Machine Intelligence. Link

An in silico method to assess antibody fragment polyreactivity. Harvey EP et al. in Nature Communications. Link

Single-shot self-supervised object detection in microscopy. Midtvedt B et al. in Nature Communications. Link

Interpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments. Gorin G et al. in Nature Communications. Link

NLoed: A Python package for nonlinear optimal experimental design in systems biology. Braniff N et al. in ACS Synthetic Biology. Link

Contemporaneous sample data tracking for the generation of genome edited cell lines. Plant AL et al. in Scientific Reports. Link

Modeling the metabolic dynamics at the genome-scale by optimized yield analysis. Luo H et al. in Metabolic Engineering. Link

🔺A computational program predicts manufacturing yields from engineered cells and even microbial communities.

Engineering polyester monomer diversity through novel pathway design. Bannister KR & Prather KLJ in Current Opinion in Biotechnology. Link

Editing DNA

A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome. Silva-Pinheiro P et al. in Nature Biomedical Engineering. Link

↑Sniper2L, a high-fidelity Cas9 variant with high activity. Kim Y-H et al. in bioRxiv. Link

🔺An engineered Cas9 protein has extremely high activity without the usual tradeoff in off-target editing of DNA.

PAM-independent ultra-specific activation of CRISPR-Cas12a via sticky-end dsDNA. Zhang W et al. in Nucleic Acids Research. Link

Editing Aspergillus terreus using the CRISPR-Cas9 system. Shih S-Y et al. in Synthetic Biology. Link

Synergic homology directed recombination by PRDM9 meiotic factor. Sanvicente-García M et al. in bioRxiv. Link

🔺Fusing Cas9 to a protein, called PRDM9, increases homologous recombination efficiencies. This study follows work published last week by Jennifer Doudna’s group.

Engineered Cells

↑A plant-derived natural photosynthetic system for improving cell anabolism. Chen P et al. in Nature. Link

🔺A synthetic photosynthesis system is engineered into mammalian cells.

↑Dynamin A as a one-component division machinery for synthetic cells. De Franceschi N et al. in bioRxiv. Link

🔺A single protein is all that is needed to split two liposomes from each other, thus providing a starting point toward synthetic, self-dividing cells.

Health

↑A randomized controlled trial showing safety and efficacy of a whole sporozoite vaccine against endemic malaria. Sirima SB et al. in Science Translational Medicine. Link

🔺A vaccine, made from whole parasites, is safe and effective against P. falciparum (malaria) infections for at least 6 months. The vaccine was tested in 80 participants in Burkina Faso who each received either three doses or saline injections.

Tumor-infiltrating lymphocyte therapy or Ipilimumab in advanced melanoma. Rohaan MW et al. in The New England Journal of Medicine. Link

Engineering antiviral immune-like systems for autonomous virus detection and inhibition in mice. Wang Y et al. in Nature Communications. Link

Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy. Zhu J et al. in Nature Communications. Link

Costs, effectiveness, and safety associated with Chimeric Antigen Receptor (CAR) T-cell therapy: Results from a comprehensive cancer center. Chacim S et al. in PLOS One. Link

Engineered drug-loaded cellular membrane nanovesicles for efficient treatment of postsurgical cancer recurrence and metastasis. Yu Y et al. in Science Advances. Link

↑Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors. Nishijima E et al. in Molecular Therapy. Link

🔺A gene therapy, injected into the eye, regenerates axons and partially restores vision in mice with glaucoma.

A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA. Doebley A-L et al. in Nature Communications. Link

🔺Cell-free DNA, circulating in the bloodstream, diagnoses estrogen receptor cancer subtypes in 139 patients with an AUC of 0.89.

IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8+ T cells to overcome immunotherapy resistance in cancer. Bae J et al. in Nature Cell Biology. Link

Structures and mechanism of chitin synthase and its inhibition by antifungal drug Nikkomycin Z by Wu Y et al. in Cell Discovery. Link

🔺The precise structure of chitin synthase and an inhibitor, Nikkomycin Z, is resolved. The structure may help to design new antifungal drugs.

Prospects for gene replacement therapies in amyotrophic lateral sclerosis. Giovannelli I et al. in Nature Reviews Neurology. Link

Logic in Living Cells

Autoinduction Expression Modules for Regulating Gene Expression in Bacillus subtilis. Xu K et al. in ACS Synthetic Biology. Link

🔺Three tools are presented to control gene expression levels in B. subtilis bacteria across a 627-fold range.

Electrogenetic signaling and information propagation for controlling microbial consortia via programmed lysis. VanArsdale E et al. in bioRxiv. Link

Longevity & Healthy Lifespan

Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling. Lee DE et al. in Nature Communications. Link

Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice. Sato T et al. in PNAS. Link

Aging is associated with a systemic length-associated transcriptome imbalance. Stoeger T et al. in Nature Aging. Link

Protein & Molecular Engineering

A general method for chemogenetic control of peptide function. Shen J et al. in Nature Methods. Link

🔺A method is presented to control small proteins, called peptides, using chemically-controllable protein domains.

Bioengineered peptibodies as blockers of ion channels. Chidipi B et al. in PNAS. Link

↑Next generation genetically encoded fluorescent sensors for serotonin. Kubitschke M et al. in Nature Communications. Link

🔺A new protein glows brightly in the absence of serotonin, but then dims when it binds to the chemical. It may be useful for neuroscience experiments that seek to track and follow neurotransmitters through the brain.

A growth selection system for the directed evolution of amine-forming or converting enzymes. Wu S et al. in Nature Communications. Link

↑Computationally-guided design and selection of high performing ribosomal active site mutants. Kofman C et al. in Nucleic Acids Research. Link

🔺A faster method to engineer the active sites of ribosomes, possibly enabling a future wherein ribosomes make more than just proteins, but also new-to-Earth polymers and materials.

The Wild

↑Robust induction of primordial germ cells of white rhinoceros on the brink of extinction. Hayashi M et al. in Science Advances. Link

🔺Cells from the endangered white rhino — of which two females remain in the wild — were induced into primordial germ cells that, one day, could be converted into sperm or eggs. The stored samples could help bring back these rhinos from extinction.

Establishment of a salt-induced bioremediation platform from marine Vibrio natriegens. Huang L et al. in Communications Biology. Link

🔺Bacteria were engineered to degrade water pollutants, including PET plastics and chlorpyrifos.

Tools & Technology

In vitro production of infectious Plasmodium falciparum sporozoites. Eappen AG et al. in Nature. Link

🔺The full lifecycle of a mosquito was recreated in the lab, without any mosquitoes. It could help produce vaccines against malaria and other diseases more quickly.

An E. coli display method for characterization of peptide–sensor kinase interactions. Brink KR et al. in Nature Chemical Biology. Link

🔺A new tool to rapidly screen molecules and proteins that activate or control gene expression in bacteria.

Hierarchical DNA branch assembly-encoded fluorescent nanoladders for single-cell transcripts imaging. Cao X et al. in Nucleic Acids Research. Link

Volumetric imaging of fast cellular dynamics with deep learning enhanced bioluminescence microscopy. Morales-Curiel LF et al. in Communications Biology. Link

🔺A light microscope and machine learning tool can, together, be used to build 3-D images of entire organisms with subcellular resolution.

Other Cool Shit

A bacterium from a mountain lake harvests light using both proton-pumping xanthorhodopsins and bacteriochlorophyll-based photosystems. Kopejtka K et al. in PNAS. Link


Musings on the Future

Tweets, essays & news articles about the future.
  • Check out this video of an “absurd microscopic murderswan.” (h/t @ATinyGreenCell).
  • A single-shot vaccine for chikungunya, called VLA1553-301, induced 99% of participants to have high levels of neutralizing antibodies 12 months after receiving the single-dose vaccination. Labiotech
  • Positive phase III trial results for people with ER-positive HER-2 negative breast cancer. Labiotech
  • An online database collects data sets maintained across 16 federal agencies into one place, making it easier than ever for scientists to request data. Science
  • A gene therapy for hemophilia B, called Hemgenix, gained U.S. approval on November 22. It’s the most expensive drug ever marketed. WIRED
  • mRNA vaccines were a lifesaver for COVID-19. Now companies are racing to design mRNA vaccines for seasonal influenza. PNAS
  • Scientific institutions should think deeply about how they spend money, who they invest in, and how they share research with the world. But there are limits to metascience. Nintil
  • Speeding up science first requires that we study how it’s done. This article looks at some recent efforts to do that. Works in Progress
  • Some argue that progress in biology is slow because it’s hard to find data, validate it, run experiments, and so forth. Emerging AI tools can help with facets of the scientific cycle. Sam Rodriques

Thanks for reading,
Niko McCarty
(Email | Twitter)