Codon Digest: GPT-4 Controls a Robot
Plus: Skin microbes target cancer.
Codon Digest is my weekly roundup of research, news, and industry highlights about engineered biology. Please send me your feedback.
“The future of architecture will be soft and hairy.”
🔥 Ten Amazing Things
(that happened this week…)
An Opentrons lab robot was programmed by a GPT-4 autonomous agent. The OpenAI model was given access to a pipetting robot through a Python API. The agent planned out chemical reactions and then used the robot to synthesize the molecules. GPT-4 automatically wrote all of the scripts needed to move the robot: Pick up tubes, aspirate samples, or dispense liquids. 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.
Skin microbes can trigger strong immune responses. It turns out that one skin microbe, called S. epidermidis, can actually trigger tumor-specific T cells. These microbes were engineered to express tumor antigens that could “elicit T cells that were licensed by the commensal immune program but specific for a tumor,” including both CD4+ and CD8+ T cells, according to the study. “In so doing, we could probe whether these T cells were capable of leaving the colonized tissue, infiltrating a tumor, and engaging in cytotoxic activity” without causing common side effects. In other words: Brush some engineered bacteria on the skin, and they activate the immune system to go fight a tumor. Wow. (More on this from Eric Topol.)
Tobacco plants were genetically-engineered to produce moth sex pheromones. This was no small feat, because moths respond to a complex mixture of two or three different molecules that must be present at specific ratios. The sex pheromones are harvested from the plants, and then hung around farms in little devices (like an Air Wick for agriculture) to draw male moths away from crops.
Short DNA strands were discovered that can specifically and tightly bind to zinc and cadmium ions. Perhaps there is now a way to use DNA to extract metals: You could fuse the DNA strands to an antibody, coat them onto electronics, and then use a column to isolate the DNA:metal compounds?
Protein-based materials, manufactured from living bacteria, could be an eco-friendly alternative to synthetic polymers made from petroleum. If you fuse mussel foot protein fragments to the ends of protein chains, it increases their strength and toughness massively. In this paper, a 57.3 kDa protein chain, with mussel foot proteins, had a high strength (481 ± 31 MPa) and toughness (179 ± 39 MJ*m−3); nearly the same as spider silk.
Hydra vulgaris is a freshwater animal that is basically immortal in the lab. It can regenerate its own limbs. Now, scientists have identified the neurons responsible for its “flipping” behavior. If you stimulate just a handful of neurons in the Hydra using optogenetics (a technique that uses light to activate action potentials), the animals do a somersault.
A computational algorithm, called ComPE, was used to create improved versions of SpyCas9, a protein used in the CRISPR gene-editing system. Specifically, ComPE was used to design four gene editor variants that had better specificity than existing variants, and caused fewer off-target edits in the genome. One of the variants had a single amino acid change at position 692.
Compact gene editors, called enOsCas12f1 and enRhCas12f1, are smaller than many existing Cas proteins and can thus be more easily delivered in a single virus for gene therapies. By engineering the sgRNA and optimizing these proteins, new variants had high editing efficiencies and low off-target effects in human cells. The editing efficiencies of enOsCas12f1 and enRhCas12f1 were 54.7% and 23.3%, respectively, compared to just 14% for the prior Cas12f1 protein. enRhCas12f1 also caused no detectable off-target edits.
Blood transfusions are equally safe if the donated blood comes from men or women. Historically, 60 percent of all donated blood has come from men, so it was unclear if there should be a preference for one or the other. This study included 8,719 patients who received red-cell transfusions.
It costs about $15 to sequence a DNA plasmid (if you use Plasmidsaurus). But now, a new paper shows how to sequence up to six plasmids in a single sample, while retaining accurate information, using Bayesian statistics. Saving money is a good thing!
📜 Papers
(* = Recommended.)
AI + Bio
*Emergent autonomous scientific research capabilities of large language models. Boiko D.A. arXiv. Read
Deep learning of genomic contexts predicts protein co-regulation and function. Hwang Y. bioRxiv. Read
ICOR: improving codon optimization with recurrent neural networks. Jain R. BMC Bioinformatics. Read
Does AlphaFold2 model proteins’ intracellular conformations? An experimental test using cross-linking mass spectrometry of endogenous ciliary proteins. McCafferty C.L. Communications Biology. Read
Basic Science
*Noncoding translation mitigation. Kesner J.S. Nature. Read
Linking genotypic and phenotypic changes in the LTEE using metabolomics. Favate J.S. eLife. Read
Ageing-associated changes in transcriptional elongation influence longevity. Debès C. Nature. Read
There’s a news article that breaks down this work.
The origins and functional effects of postzygotic mutations throughout the human life span. Rockweiler N.B. Science. Read
Structural basis of sensory receptor evolution in octopus. Allard C.A.H. Nature. Read
Germline-encoded amino acid–binding motifs drive immunodominant public antibody responses. Shrock E.L. Science. Read
Spatial transcriptome uncovers rich coordination of metabolism in E. coli K12 biofilm. Wang T. Nature Chemical Biology. Read
Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability. Mansilla S.F. Science Advances. Read
Expanding known viral diversity in the healthy infant gut. Shah S.A. Nature Microbiology. Read
Broad compatibility between yeast UAS elements and core promoters and identification of promoter elements that determine cofactor specificity. Schofield J.A. & Hahn S. Cell Reports. Read
RIP-PEN-seq identifies a class of kink-turn RNAs as splicing regulators. Li B. Nature Biotechnology. Read
Genome-wide CRISPR screens identify ILF3 as a mediator of mTORC1-dependent amino acid sensing. Yan G. Nature Cell Biology. Read
Biological Engineering
*Temporally resolved transcriptional recording in E. coli DNA using a Retro-Cascorder. Lear S.K. Nature Protocols. Read
*Open-endedness in synthetic biology: a route to continual innovation for biological design. Stock M & Gorochowski T. Preprint. Read
Small DNAs that specifically and tightly bind transition metal ions. Zhou M. JACS. Read
Bi-terminal fusion of intrinsically-disordered mussel foot protein fragments boosts mechanical strength for protein fibers. Li J. Nature Communications. Read
Programming bacteria for multiplexed DNA detection. Chen Y-Y. Nature Communications. Rea
Biodeterioration of pre-treated polypropylene by Aspergillus terreus and Engyodontium album. Samat A.F. npj Materials Degradation. Read
Characterizing and utilizing oxygen-dependent promoters for efficient dynamic metabolic engineering. Wichmann J. Metabolic Engineering. Rea
In vitro transcription/translation-coupled DNA replication through partial regeneration of 20 aminoacyl-tRNA synthetases. Hagino K & Ichihashi N. ACS Synthetic Biology. Read
Trimming the genomic fat: minimising and re-functionalising genomes using synthetic biology. Xu X. Nature Communications. Read
Reprogramming of human peripheral blood mononuclear cells into induced mesenchymal stromal cells using non-integrating vectors. Chen W. Communications Biology. Read
Versatile microbial communities rapidly assimilate ammonium hydroxide-treated plastic waste. Schaerer L.G. Journal of Industrial Microbiology and Biotechnology. Read
The Brain
*Peptide-driven control of somersaulting in Hydra vulgaris. Yamamoto W & Yuste R. Current Biology. Read
Neural cell isolation from adult macaques for high-throughput analyses and neurosphere cultures. Wei J-R. Nature Protocols. Read
Open science and data sharing in cognitive neuroscience with MouseBytes and MouseBytes+. Memar S. Scientific Data. Read
N-glycoproteomics of brain synapses and synaptic vesicles. Bradberry M.M. Cell Reports. Read
Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct. Gehrlein A. Nature Communications. Read
Genetic Engineering
*Computationally engineered CRISPR-SpyCas9 high-fidelity variants with improved specificity and reduced non-specific DNA damage. Rabinowitz R. bioRxiv. Read
*Optimization of Cas9 activity through the addition of cytosine extensions to single-guide RNAs. Kawamata M. Nature Biomedical Engineering. Read
Engineered CRISPR-OsCas12f1 and RhCas12f1 with robust activities and expanded target range for genome editing. Kong X. Nature Communications. Rea
Chromatin context-dependent regulation and epigenetic manipulation of prime editing. Li X. bioRxiv. Read
CRISPR/Cas9-mediated genome editing via homologous recombination in a centric diatom Chaetoceros muelleri. Yin W & Hu H. ACS Synthetic Biology. Read
A modular cloning toolkit including CRISPRi for the engineering of the human fungal pathogen and biotechnology host Candida glabrata. Billerbeck S. ACS Synthetic Biology. Read
Easy modular integrative fuSion-ready Expression (Easy-MISE) toolkit for fast engineering of heterologous productions in Saccharomyces cerevisiae. Maestroni L. ACS Synthetic Biology. Read
Health
*Engineered skin bacteria induce antitumor T cell responses against melanoma. Chen Y.E. Science. Read
Effect of donor sex on recipient mortality in transfusion. Chassé M. The New England Journal of Medicine. Read
A bioorthogonal antibody-based chemically-induced-dimerization switch for therapeutic application. Martinko A.J. bioRxiv. Read
Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice. Hu X. Nature Communications. Read
Development of a translatable gene augmentation therapy for CNGB1-Retinitis Pigmentosa. Occelli L.M. Molecular Therapy. Read
Safety and dose escalation of the targeted oncolytic adenovirus OBP-301 for refractory advanced liver cancer: Phase I clinical trial. Heo J. Molecular Therapy. Read
The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection. Arieta C.M. Cell. Read
High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike. Tan T.J.C. Nature Communications. Read
An RNA-based system to study hepatitis B virus replication and evaluate antivirals. Yu Y. Science Advances. Read
[Comment] Delivering the next generation of cancer immunotherapies with RNA. Raimondo T.M. Cell. Read
Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models. Cao X. Science Translational Medicine. Read
Antisense oligonucleotide therapy for H3.3K27M diffuse midline glioma. Zhang Q. Science Translational Medicine. Read
Effectiveness of a bivalent mRNA vaccine booster dose to prevent severe COVID-19 outcomes: a retrospective cohort study. Arbel R. The Lancet Infectious Diseases. Read
Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trial. Jenkin D. The Lancet Infectious Diseases. Read
Antibodies against the Ebola virus soluble glycoprotein are associated with long-term vaccine-mediated protection of non-human primates. Gunn B.M. Cell Reports. Read
Extracellular vesicles engineering by silicates-activated endothelial progenitor cells for myocardial infarction treatment in male mice. Yu B. Nature Communications. Read
Plants & Algae
*Tunable control of insect pheromone biosynthesis in Nicotiana benthamiana. Kallam K. Plant Biotechnology Journal. Read
Software & Computational Models
Identifying widespread and recurrent variants of genetic parts to improve annotation of engineered DNA sequences. McGuffie M.J. & Barrick J.E. bioRxiv. Read
TFBMiner: A user-friendly command line tool for the rapid mining of transcription factor-based biosensors. Hanko E.K.R. ACS Synthetic Biology. Read
Large-scale correlation network construction for unraveling the coordination of complex biological systems. Becker M. Nature Computational Science. Read
A coarse-grained bacterial cell model for resource-aware analysis and design of synthetic gene circuits. Sechkar K. bioRxiv. Read
A hybrid in silico/in-cell controller for microbial bioprocesses with process-model mismatch. Ohkubo T. bioRxiv. Read
Tools and Methods
*Barcode-free multiplex plasmid sequencing using Bayesian analysis and nanopore sequencing. Uematsu M & Baskin J.M. bioRxiv. Read
And see the Python notebook, which walks you through how to pool multiple plasmids together and sequence all of them at once.
Comparison of transformations for single-cell RNA-seq data. Ahlmann-Eltze C & Huber W. Nature Methods. Read
Lustro: High-throughput optogenetic experiments enabled by automation and a yeast optogenetic toolkit. Harmer Z.P. & McClean M.N. bioRxiv. Read
Local generation and efficient evaluation of numerous drug combinations in a single sample. Elgart V & Loscalzo J. eLife. Read
Spatiotemporally resolved transcriptomics reveals the subcellular RNA kinetic landscape. Ren J. Nature Methods. Read
Time-resolved assessment of single-cell protein secretion by sequencing. Wu T. Nature Methods. Read
GlycoCAP: A cell-free, bacterial glycosylation platform for building clickable azido-sialoglycoproteins. Thames A.H. ACS Synthetic Biology. Rea
Controlling protein stability with SULI, a highly sensitive tag for stabilization upon light induction. Mao M. Nature Communications. Read
A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon. Tan L. Science Advances. Read
A high throughput bispecific antibody discovery pipeline. Segaliny A.I. Communications Biology. Read
Single-shot time-folded fluorescence lifetime imaging. Kapitany V. PNAS. Read
TReSR: A PCR-compatible DNA sequence design method for engineering proteins containing tandem repeats. Davey J.A. & Goto N.K. PLOS One. Read
Gas-modulating microcapsules for spatiotemporal control of hypoxia. Molley T.G. PNAS. Read
Full-length circular RNA profiling by nanopore sequencing with CIRI-long. Hou L. Nature Protocols. Read
Just for Fun
High protein-containing new food by cell powder meat. Choi B. npj Science of Food. Read
Retracted Covid-19 articles: significantly more cited than other articles within their journal of origin. Taros T. Scientometrics. Read
A swallowable X-ray dosimeter for the real-time monitoring of radiotherapy. Hou B. Nature Biomedical Engineering. Read
📰 News
A French company, called Neoplants, is selling genetically engineered pothos house plants that purify the air and remove volatile organic compounds, like benzene and toluene. More than 30,000 people have already signed up for the waiting list. There’s just one problem: “…a bedroom of approximately 200 square feet would need as many as 315 individual plants to bring formaldehyde (and other VOC) levels down by 50 percent. To get a 90 percent reduction would require more like 2,800 plants. Scale that up to a whole flat or house, and you’re nurturing a dense jungle.” Will Pritchard for WIRED. Read
ValleyDAO, a decentralized organization that funds synthetic biology projects, opened its community token auction. The auction runs until April 23rd. I don’t own any tokens. Read
A purple tomato, made by Norfolk Healthy Produce, was genetically-engineered to contain high levels of antioxidants. And soon, it will be in grocery stores. Here’s how that came to be. John Cumbers for Genetic Literacy Project. Read
“A California man is the first person in the Western US to have a confirmed infection with a curious bacterium that has lurked in the region for over two decades” — Borrelia miyamotoi, a spiral-like microbe that causes Lyme disease. Beth Mole for Ars Technica. Read
Elizabeth Holmes, who was convicted on three counts for defrauding investors during her time as CEO of Theranos, had her bail request denied. She will remain in prison for now. Beth Mole for Ars Technica. Read
Companies founded entirely by women raise 2.1% of all VC investments. Dominic-Madori Davis for Tech Crunch. Read
Also, the latest batch of YC companies can, overwhelmingly, be described by the singular phrase: “maybe AI can do this?” AI to answer the phone. AI to tutor kids. AI to make artwork for video games. AI to write sales emails. One company that does look intriguing is Meru, which is building a platform to train your own large-language models. Devin Coldewey for Tech Crunch. Read
A few months ago, scientists discovered an Asgard archaea, thought to be the “closest known” relative of eukaryotes. It was just the second example to be found and studied. Now, there is a very strange competition happening in the ultra-niche Asgard biology space as laboratories race to culture these organisms: “Samples aren’t shared; growth strategies are tightly guarded secrets.” Joshua Sokol for Quanta Magazine. Read
Postdocs who work in an HHMI laboratory now get a minimum salary of $70,000. HHMI News. Read
🧠 Musings
I’ve gone down a biodesign rabbit hole, and have been trying to learn everything possible about the intersection of genetic engineering and creative media. I put out a call on Twitter for book recommendations, and want to share them with you here.
Biodesign: Nature + Science + Creativity by William Myers
Grow the Future by the Biodesign Challenge team
Nature: Collaborations in Design by Cooper Hewitt
Speculative Everything by Anthony Dunne and Fiona Raby
Synthetic Aesthetics by Ginsberg, Calvert, Schyfter, Elfick & Endy
📈 Companies
RegenXBio, a Maryland-based gene therapy company, received FDA fast track designation for RGX-202, a one-time therapy for Duchenne muscular dystrophy. Read
ImmuneBridge, a biotech company focused on cancer therapies, raised $12 million in seed funding. Read
Sana Biotechnology, a company that is engineering cells to treat diseases, saw its stock rise 49.4% for the week after announcing positive pre-clinical results for two cell therapies: SC451 for Type 1 diabetes and SC262 for B-cell tumors. Read
Function Oncology, a company using CRISPR to make precision cancer therapies, launched with $28 million. Read
Moderna, a biotechnology company developing mRNA vaccines, announced that its seasonal flu vaccine, mRNA-1010, “did not meet the statistical threshold necessary to declare early success” in a Phase 3 trial. No safety concerns were identified. Read
In Q1 2023, there was an 87% increase in biopharma layoffs, with 56 companies cutting staff compared to 30 in the same period of 2022. Read
TORL BioTherapeutics, an oncology company focused on antibody-drug conjugates and monoclonal antibodies, raised $158 million in a Series B round. Read
Alentis Therapeutics, a biotech company developing Claudin-1 antibodies for organ fibrosis and tumors, raised $36 million in a Series C. Read
Aer Therapeutics, a University of California, San Francisco lab spinout developing an inhaled small molecule drug for chronic obstructive pulmonary disease, raised $36 million in a Series A. Read
Vitarka Therapeutics, a company developing a non-viral drug delivery technology, raised £1.27 million ($1.58 million) in equity from SOSV, the UK Innovation & Science Seed Fund, and grant funding from Innovate UK. Read
Ginkgo Bioworks is going to build out biosecurity technologies in the Democratic Republic of the Congo. Read
Thanks for reading,
— 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.