Bridge recombinases are naturally occurring RNA-guided DNA recombinases that we previously demonstrated can programmably insert, excise, and invert DNA in vitro and in Escherichia coli. In this study, we report the discovery and engineering of the bridge recombinase ortholog ISCro4 for universal rearrangements of the human genome.
Obtaining novel antibodies against specific protein targets is a widely important yet experimentally laborious process. Here, we introduce Germinal, a broadly enabling generative framework that designs antibodies against specific epitopes with nanomolar binding affinities while requiring only low-throughput experimental testing.
Genome language models have emerged as a promising strategy for designing biological systems, but their ability to generate functional sequences at the scale of whole genomes has remained untested. Here, we report the first generative design of viable bacteriophage genomes.
Existing ENPP1 inhibitors have been optimized for prolonged systemic residence time rather than effective target inhibition within tumors. Here, we report the characterization of STF-1623, a highly potent ENPP1 inhibitor with an exceptionally long tumor residence time despite rapid systemic clearance, enabled by its high binding affinity and slow dissociation rate.
Here, we introduce STATE, a transformer model that predicts perturbation effects while accounting for cellular heterogeneity within and across experiments. State predicts perturbation effects across sets of cells and is trained using gene expression data from over 100 million perturbed cells.
The STING innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, it remains unclear which mechanistic step(s) are crucial for inhibition of downstream signaling. Here we report that C91 palmitoylation is not universally necessary for human STING signaling.
We introduce Evo 2, a biological foundation model trained on 9.3 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life. We train Evo 2 with 7B and 40B parameters to have an unprecedented 1 million token context window with single-nucleotide resolution.
The genome is a sequence that encodes the DNA, RNA, and proteins that orchestrate an organism's function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report scaling laws on DNA to complement observations in language and vision.
The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA), a ubiquitous danger signal, to produce interferon. However, STING activation must be tightly controlled because aberrant interferon production leads to debilitating interferonopathies. Here, we discover PELI2 as a crucial negative regulator of STING.
Genomic rearrangements, encompassing mutational changes in the genome such as insertions, deletions, or inversions, are essential for genetic diversity. We report that IS110 insertion sequences, a family of minimal and autonomous mobile genetic elements, express a structured non-coding RNA that binds specifically to their encoded recombinase.