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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Read the full preprint below 👇 If you're interested in the interface of bioengineering, DNA and virtual cell foundation models, and agentic reasoning, shoot me a note. We're hiring postdocs and ML researchers and starting some crazy new projects

www.biorxiv.org/content/10.1...

Megabase-scale human genome rearrangement with programmable bridge recombinases

Bridge recombinases are a class of naturally occurring RNA-guided DNA recombinases. We previously demonstrated they can programmably insert, excise, and invert DNA in vitro and in bacteria. Here, we r...

www.biorxiv.org

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

This work was a wonderful collaboration with Silvana Konermann, led by star graduate student Nick Perry with key contributions from the amazing Liam Bartie, Dhruva Katrekar, Gabe Gonzalez, Matt Durrant, James Pai, Alison Fanton, Masa Hiraizumi, Chiara Ricci-Tam, and Hiroshi Nishimasu

Arc is on 🔥

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Bridge recombinases can modify the genome from single gene insertions to megabase-sized rearrangements

We're excited about programmable genome design at unprecedented length scales, especially when combined with AI-generated DNA sequences of high complexity (e.g. Evo 2)

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Most people think of recombinases for payload insertion (e.g. of CARs or corrective genes)

We provide a therapeutic proof-of-concept with bridge-mediated excision of the BCL11A enhancer for sickle cell anemia and of expanded repeat sequences found in Friedreich's ataxia

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

But unlike other tools, bridge editing is not limited to insertion! We use IS622 for programmable, precise, and scarless genome rearrangements, inverting up to 0.93 Mb and excising up to 0.13 Mb

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

We then performed a systematic deep mutational scan of IS622 and combined a rationally engineered, high activity recombinase mutant with our enhanced bridge RNAs to demonstrate 20% insertion efficiency into the human genome

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Using these enhanced bridge RNAs, we discovered design principles for maximizing the specificity of insertion into the human genome, achieving as high as 82% specificity genome-wide

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

In a tour de force of molecular engineering, our team conducted computational ortholog mining, human cell activity screening, and structure-guided bridge RNA engineering to enhance the activity of IS622, a bridge system that showed promising but low activity in human cells

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Bridge recombination systems are elegant molecular tools that utilize a recombinase enzyme and a programmable bridge RNA to "bridge" and recombine two distinct DNA molecules

This is a universal mechanism for insertion, excision, or inversion of any two DNA sequences

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pdhsu.bsky.social @pdhsu.bsky.social · May 15

Genomes encode biological complexity, which is determined by combinations of DNA mutations across millions of bases

In new work @arcinstitute.org, we report the discovery and engineering of the first programmable DNA recombinases capable of megabase-scale human genome rearrangement

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Reposted

Andrew Dunn @andrewedunn.bsky.social · Apr 30

This was a fun one — new Endpoints Slack interview with @pdhsu.bsky.social :

endpts.com/endpoints-sl...

The Endpoints Slack interview: Arc Institute's Patrick Hsu on investing, AI and new ways of research

An interview with Patrick Hsu, 31, Harvard PhD grad and CRISPR pioneer, who co-founded Arc Institute and helped develop Evo 2, a biology-focused AI model.

endpts.com

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pdhsu.bsky.social @pdhsu.bsky.social · Mar 24

are there good CROs for cell line engineering and generation?

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Reposted

Arc Institute @arcinstitute.org · Feb 25

Today, we're launching the Arc Virtual Cell Atlas, a growing resource for computation-ready single-cell measurements. arc-website-git-ben-virtual-cell-atlas-tool-arc-institute.vercel.app/news/news/ar...

Arc Virtual Cell Atlas launches, combining data from over 300 million cells | Arc Institute

Arc Institute today launched the Arc Virtual Cell Atlas, a growing resource for computation-ready single-cell measurements, starting with data from over 300 million cells. The initial release of the A...

arc-website-git-ben-virtual-cell-atlas-tool-arc-institute.vercel.app

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Reposted

Yusuf Roohani @yusufroohani.bsky.social · Feb 25

At the @arcinstitute.org we are building AI models of cell state from the ground up, rethinking every step, from data generation to biologically relevant evaluation

Today we launch scBaseCamp, the largest public repository of single cell RNAseq data, uniformly processed from raw sequencing reads.

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Reposted

Hani Goodarzi @genophoria.bsky.social · Feb 25

@thejohnnyyu.bsky.social, @therealnima.bsky.social, and I, are excited to tell you about Tahoe-100M! The largest publicly available single-cell dataset that measures the effect of 1200 genes on 50 cell line models. The Vevo team has outdone itself. #Tahoe100M www.biorxiv.org/content/10.1...

Tahoe-100M: A Giga-Scale Single-Cell Perturbation Atlas for Context-Dependent Gene Function and Cellular Modeling

Building predictive models of the cell requires systematically mapping how perturbations reshape each cell's state, function, and behavior. Here, we present Tahoe-100M, a giga-scale single-cell atlas ...

www.biorxiv.org

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Reposted

Hani Goodarzi @genophoria.bsky.social · Feb 25

Watch @thejohnnyyu.bsky.social @therealnima.bsky.social (@vevotherapeutics.bsky.social), @pdhsu.bsky.social , Dave Burke and I (@arcinstitute.org) talking about virtual cells, and how #Tahoe100M, now on. @arcinstitute.org's Virtual Cell Atlas, can change the game!

www.youtube.com/watch?v=ak_f...

No Priors Ep. 103 | With Vevo Therapeutics and the Arc Institute

YouTube video by No Priors: AI, Machine Learning, Tech, & Startups

www.youtube.com

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Reposted

Fay Lin @faylinphd.bsky.social · Feb 19

New from @arcinstitute.org is "the largest publicly available #AI model for biology to date"!

Evo 2 now includes information from all domains in life to expand its capabilities in generative functional genomics. @pdhsu.bsky.social @brianhie.bsky.social

tinyurl.com/3t83vseh

Arc Institute’s AI Model Evo 2 Designs the Genetic Code Across All Domains of Life

Evo 2 now includes information from humans, plants, and other eukaryotic species to expand its capabilities in generative functional genomics.

tinyurl.com

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

This was an insane team effort between Arc and Nvidia that convened machine learning and computational biology researchers across Stanford, UC Berkeley, and UCSF. Especially grateful to Jensen Huang for his belief and support of this vision and labor of love, and the entire Evo 2 team below

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

Finally, if Evo 2 sounded exciting, @arcinstitute.org
is hiring. Check out open Arc jobs at arcinstitute.org/jobs or just email me directly. Our research group is hiring in molecular machine learning and the interface of computational and synthetic biology

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

and check out our blog post! arcinstitute.org/news/blog/evo2

AI can now model and design the genetic code for all domains of life with Evo 2 | Arc Institute

Arc Institute develops the largest AI model for biology to date in collaboration with NVIDIA, bringing together Stanford University, UC Berkeley, and UC San Francisco researchers

arcinstitute.org

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

and a few more :)

NVIDIA BioNeMo: github.com/NVIDIA/bione...
NVIDIA NIM (Generation): build.nvidia.com/nvidia/evo2-...
NVIDIA NIM (Forward): build.nvidia.com/arc/evo2-40b
HuggingFace Evo 2 40B: huggingface.co/arcinstitute...
HuggingFace Evo 2 7B: huggingface.co/arcinstitute...

GitHub - NVIDIA/bionemo-framework: BioNeMo Framework: For building and adapting AI models in drug discovery at scale

BioNeMo Framework: For building and adapting AI models in drug discovery at scale - NVIDIA/bionemo-framework

github.com

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

Here are some useful links:

Evo 2 preprint: arcinstitute.org/manuscripts/...
Evo Designer: arcinstitute.org/tools/evo/ev...
Evo Mech Interp Visualizer: arcinstitute.org/tools/evo/ev...
Evo 2 code: github.com/arcinstitute...

Manuscript | Arc Institute

Arc Institute is a independent nonprofit research organization headquartered in Palo Alto, California.

arcinstitute.org

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

DNA is just the beginning. In middle school, we learn that genotype and the environment collaborate to create phenotype. We are incorporating Evo 2's understanding of genetic variation into Arc's virtual cell models that can be used for drug discovery and target ID

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

We're excited to see what the research community builds on top of this foundation model to enable the biological "app store"

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pdhsu.bsky.social @pdhsu.bsky.social · Feb 19

Beyond pretraining scale, Evo 2 also scales at inference time. We demonstrate "generative epigenomics" by controlling the position and width of predicted chromatin accessibility to encode Morse code messages in the epigenome. Can you guess what's written below? .- .-. -.-.

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