Thank you Manel 🙏

EU relaxes rules for gene-edited crops The new laws break away from 20-year-old restrictive GMO directives to give an official nod to plants made with new genomic techniques nature.com/articles/s41587-0…

Mutational consequences of perturbing DNA repair and chromatin state in Arabidopsis biorxiv.org/content/10.64898… Fantastic job Cullan!

Here is a neat story led by Alex Tadros on the history of Arabidopsis laboratory stocks. They can be diverged by over 100 generations! Genetic and epigenetic divergence among Arabidopsis thaliana Col-0 laboratory lineages since the 1950s biorxiv.org/content/10.64898…

Amazing convergence of two NIH funded studies using orthogonal approaches to discover microglia switch in the brain during aging nature.com/articles/s41586-0… @NIHDirector_Jay

Only about a quarter of human diseases have an approved therapy. By some estimates it's a few percent. Most of those treatments slow a disease rather than stop it. Closing that gap is what the AI-cures-everything story promises. Build a system smart enough and the cures hidden in what we already know will fall out. I have worked at the intersection of machine learning and biology for three decades, and I believe #AI will eventually transform human health. The capabilities arriving now are extraordinary. But the promise rests on an assumption that is simply false: that we already understand human biology well enough for a clever enough reasoner to find the answers in it. We don't. More than 90% of drugs entering clinical trials fail, a number that has barely moved in decades. In the large majority of those failures the molecule was engineered just fine. The mechanism it targeted was wrong. We are doing a pretty good job at manufacturing keys, but they are generally for the wrong locks. And because nobody wants to fail in the clinic, the industry has retreated to the locks it already trusts: 38 targets now have more than 50 programs against each of them, while the number of novel targets advanced per year fell from roughly 100 in 2015 to about 30 in 2024. AI will not reason its way past this. Biology wasn't engineered. It is the product of billions of years of messy, stochastic evolution, and the variation that produced is too vast and too idiosyncratic to work out in the abstract. You have to measure it. Aimed at a biology this thinly sampled, AI will mostly help us generate failures faster. I founded @insitro because getting to the right locks requires a different kind of system. We generate multimodal human and cellular data at scale, use machine learning to find causal drivers of disease, and test those hypotheses experimentally. Virtual Human™ is built for causal discovery; TherML™ turns what it finds into the right therapeutic intervention. It is working: first-in-class programs internally and with partners, three #ALS targets that Virtual Human™ identified and @bmsnews nominated, and additional collaborations with @EliLillyandCo and @GileadSciences . Today we are launching Deep Phenotype: Scaled Biology, Deep Causality. Issue one is "Drug Discovery Has No Magic Wands," the first half of a two-part essay on the magical thinking currently running through our field and what I think it will actually take. After that you will hear from insitro's own scientists and engineers, people who work across computation and experiment because the problem requires both. Getting this right is hard, and we do not have all of it worked out. I hope you will follow along and think it through with us. DeepPhenotype.Substack.com

We had such great time at the #GRC meeting on Neuroepigenetics! Beautiful nature in NH, good food & exceptional science. @themazelab and I are future vice chairs! So excited to help this meeting & community grow! ❤️ 🙏all! @BarcoLab @JoeEcker @PhilippMews @apombo1 @CreminsLab

A heartbreaking realisation that @andyburnham's father will likely not ever recognise that his son has become Prime Minister. For about 10 years now, Alzheimer's and other dementias have been the leading cause of death in the UK (outside of the pandemic) - 10 years! The disease's lethality is only eclipsed by the extreme toll it takes emotionally and socially. The UK is well-positioned to build the cures for this disease and many others, for the benefit of our country and the wider world. With leading research institutions already like the @UKDRI and the growing exceptionality of AI led by @KanishkaNarayan, we have real reason to have hope. This is what we're deeply committed to at @PrimaMente. No one should be robbed like this.

Yes, good question. Mutations are acquired over time by all cells in the body. These mutations are totally random and unique to each cell. Therefore, they are typically detectable only with single cell WGS or after clonal expansion, and PACT only tracks expanded clones. In parallel, the phenotype of single cells can be measured in many ways, such as snRNA, snATAC, or snm3C-seq (methylation + chromatin conformation). What Zemke et al. found is that microglia in aged individuals are very similar to human monocytes. @JoeEcker science.org/doi/10.1126/scie… This similarity is only detectable via methylation, not snRNA or snATAC. ~All human monocytes and microglia appear to have stereotyped methylation signatures that are quite reproducible across individuals. The most obvious explanation for this is that aged human microglia may be highly similar to monocytes because the microglia have been replaced by monocyte-derived cells. However, methylation can change over time, so it is quite challenging to fully prove this. However, the somatic mutation approach does provide definitive proof of a bone marrow origin for the expanded clones of cells that are trackable via PACT (or mtscATAC-seq). Future work will be needed to fully unify the strengths of both approaches - stay tuned!

Amazing convergence of finding using orthogonal approaches - congrats Julia et al!

Single-Cell Atlas Simultaneously Maps 3D Genome Architecture and DNA Methylation The NIH 4D Nucleome consortium aims to extend this kind of mapping into the fourth dimension: time @JoeEcker @salkinstitute @arcinstitute #AI #DNAmethylation #epigenetics hubs.li/Q04qRpqL0

Gaining therapeutic access to the human brain is one of the biggest unsolved problems in biomedical science. Today @nature, we uncover a massive influx of immune cells into the human brain during aging, revealing that the brain is more accessible than previously thought. 1/ nature.com/articles/s41586-0…

Serendipitously, Nathan Zemke, Bing Ren, and @JoeEcker discovered the same phenomenon using a different approach: single cell methylation. Collectively, these data show that the replacement of yolk sac microglia by monocytes starts in middle age and is ~complete by age ~80. 5/ science.org/doi/10.1126/scie…

Epigenetics Update - Human body single-cell atlas of three-dimensional genome organization and DNA methylation u.epigenome.us/lCLovkSu @Jesse_R_Dixon and Joseph R. Ecker (@salkinstitute) in @ScienceMagazine #Epigenetics #DNAm --- Gain deeper insights; epigenometech.com

And you need single cell (not bulk) methylation atlases of all body cell types in order to “see” the epigenetic cell origins of microglia and other lineages -it’s written on top of the genome doi.org/10.1126/science.adx0…

Many thanks to @zhou_jingtian, May Wu, @Jesse_R_Dixon & the entire @salkinstitute team! Even before publication, Nathan Zemke (UCSD/Ren lab) et al. used the methylation data to ID a yoke sac to monocyte microglial switch in the aging hippocampus also out today in the @4DN package

Meet Neil Shubin, the new president of @theNASciences. In his introductory message, he reflects on our 163-year tradition of serving the nation through independent scientific advice — and his vision for the future. Watch: ow.ly/WPjc50ZqRpw

Strands of DNA-like thread coil, loop, and spill upward, evoking the genome's dynamic three-dimensional architecture within the nucleus of a living cell. This special issue, with papers in Science and @ScienceAdvances, features single-cell and multiomic studies from the National Institutes of Health Common Fund's 4D Nucleome Program, which examines a fourth dimension of nuclear organization—how this folded structure shapes cell identity, shifts across development and aging, and goes awry in disease. Learn more: scim.ag/4wZDL05

Excited to share our latest preprint! Congrats to Jie Yao for leading this work and the entire team for a fantastic collaboration. 🌱🧬 Sequence-based modeling of plant epigenomes reveals cell-type-specific cis-regulatory grammar biorxiv.org/content/10.64898…

Excited to share our recent paper (doi.org/10.1016/j.cell.2026.…)! In this multi-year effort, we developed RT&T-AMP-MERFISH, enabling whole-transcriptome-scale, isoform-resolved single-cell spatial transcriptomics and imaging ~33,000 RNAs in the brain.