Large serine recombinases can mediate direct, site-specific genomic integration of multi-kilobase DNA sequences without a pre-installed landing pad, albeit with low insertion rates and high off-target activity. Here we present an engineering roadmap for jointly optimizing their DNA recombination efficiency and specificity.
The androgen receptor is a critical driver of prostate cancer. Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi screens to systematically identify genes that modulate AR protein levels.
Here, we introduce the EnCodon model series within CodonFM, a family of large foundation models trained on more than 130 million coding sequences spanning over 22,000 species, designed to learn the contextual grammar of codon usage directly from sequence.
Here, we develop an all-RNA platform for efficient, durable and multiplexed epigenetic programming in primary human T cells, stably turning endogenous genes off or on using CRISPRoff and CRISPRon epigenetic editors. We achieve epigenetic programming of targeted genomic elements without the need for sustained expression of CRISPR systems.
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.
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.
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.
Virtual cells are an emerging frontier at the intersection of artificial intelligence and biology. A key goal of these cell state models is predicting cellular responses to perturbations. The Virtual Cell Challenge is being established to catalyze progress toward this goal.
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.