Paper notes, opinionated essays, and a primer built from the ground up — keeping the parts of the field that actually hold up.
Hematopoietic stem cells, gene editing, and the road from bench to clinic.
How AI is starting to change the way biomedical research actually gets done.
研究者用配体感知的 de novo 蛋白设计，为三种 Janelia Fluor 染料造出小型、纳摩尔亲和力且彼此正交的 NovoTag，并把蛋白口袋进一步改造成寿命调节器、共价标签和染料诱导二聚系统。
Ligand-aware de novo protein design produced compact, nanomolar-affinity and mutually orthogonal NovoTags for three Janelia Fluor dyes, then turned their binding pockets into lifetime modulators, a covalent tag and a dye-induced dimerization system.
这篇尚未同行评议的预印本用 prime editing 给人 CD34+ 造血干细胞装上 CD117 E73K 护盾，再用 CIM058 清除未保护细胞，在人源化 β-地中海贫血小鼠中实现无 busulfan 的预处理与体内富集。
This unreviewed preprint uses prime editing to give human CD34+ cells a CD117 E73K shield, then pairs them with CIM058 to deplete unprotected cells and enrich the edited graft in a humanized β-thalassemia mouse model.
研究者把结构逆折叠与进化约束结合，设计出与天然 TnpB 显著分化、仍能在细菌、植物和人细胞中工作的 SynTnpB 基因编辑器。
Structure-conditioned inverse folding and evolutionary constraints generate sequence-divergent SynTnpB editors that remain active in bacterial, plant and human cells.
这项 Nature Genetics 研究用体内 Perturb-seq 并行扰动 79 个抑郁症 GWAS 风险基因，并在人类数据中找到一个共同指向神经元催产素 OXTR–ERK 信号下降的风险基因亚群。
An in vivo Perturb-seq screen of 79 MDD GWAS risk genes identifies a patient-matched subgroup converging on weakened neuronal oxytocin OXTR–ERK signaling.
这项 Nature 研究用 KIT 表位编辑保护移植 HSPC，再用抗 KIT 抗体清除未编辑细胞，把非基因毒性清髓、体内选择和 BCL11A 相关胎儿血红蛋白治疗接到同一条路径上。
This Nature study uses KIT epitope editing to protect donor HSPCs, then anti-KIT antibodies to remove unedited cells, linking non-genotoxic conditioning, in vivo selection and BCL11A-based fetal-haemoglobin therapy.
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2019年的研究发现,健康人群中最高达78%的人已携带能识别Cas9的抗体或T细胞——这套源自两种常见致病菌的免疫记忆,在体外一次性RNP编辑里被巧妙避开,却在追求长期体内表达的下一代基因编辑疗法门前显出真实分量。
A 2019 study found that up to 78% of healthy people already carry antibodies or T cells that recognize Cas9 — immune memory left by two common pathogenic bacteria that ex vivo, one-time RNP editing quietly sidesteps, but that shows its real weight at the door of next-generation therapies aiming for sustained in vivo expression.
全球第一款获批的CRISPR疗法Casgevy如何编辑BCL11A关掉致病开关、两项3期试验交出97%和91%的达标率,以及220万美元一次的治疗为何近两年后才真正开始放量。
How Casgevy, the world's first approved CRISPR therapy, edits BCL11A to silence the switch that shuts off fetal hemoglobin, why two phase 3 trials produced 97% and 91% response rates, and why a $2.2 million one-time treatment took nearly two years to actually start reaching patients.
Arc、CZI、DeepMind 都在押注 AI 虚拟细胞。但把尺子对准最硬的那个结果：Arc 自己的挑战赛承认模型『还没能稳定超过朴素基线』，一篇 Genome Biology 评测里基础模型甚至输给『挑高变基因』。
Arc, CZI, and DeepMind are all betting on the AI virtual cell. But hold the ruler to the hardest result: Arc's own challenge admits models 'do not yet consistently beat naive baselines,' and a Genome Biology evaluation shows the foundation models lose to simply picking highly variable genes.
Doudna 团队用 AI 造出编辑效率反超天然酶的 SynTnpB，但论文标题里的 guided 才是最诚实的信号：AI 压缩的是酶设计这段可廉价验证的前端，通往体内安全那道贵门还没碰。
Doudna's lab built SynTnpB, an AI-designed nuclease that out-edits its natural template. But the honest signal is the word in the paper's title — guided: AI compressed the cheap front end of enzyme design, and never touched the expensive gate of in-vivo safety.
通用 agentic 科研平台会把“会用 AI 做科研”变成基础能力，真正的护城河会转向问题定义、证据判断和验证设计。
General agentic science platforms will turn AI-assisted research into baseline literacy; the moat shifts to question quality, evidence judgment, and validation design.