Long time lurker, breaking a decade of silence to share an essay on what I've learned from scientists about making medicines (spoiler: it's hard) and why the future looks bright (also spoiler: AI) 🧵

Deeply saddened by the loss of David Baltimore - a mentor, role model, and scientific giant who shaped so many of us. Most memorably, I was sitting next to David, a month after I started as a baby Assistant Professor, when I learned about CRISPR. His kindness and wisdom will be

Check out our new paper, out today in @NatureBiotech! We present SPEAR, a modular system for biomolecular cargo delivery with bacterial "nanosyringes". Thanks to my advisor, @zhangf, and amazing undergraduate (now graduate) student @vicy_ang https://t.co/JKjeRIOuAL

Can we use RNA to insert kilobases of DNA into the human genome, opening up a new way to engineer cells or treat disease? Excited to share our latest work turning a retrotransposon (a “jumping gene” with an RNA intermediate) from songbirds into a genome editing tool. 🧵 (1/7)

This work was led by the phenomenal team of @GuilhemFaure, Makoto Saito, @maxewilkinson, in collaboration with Natalia Quinones-Olvera, @Peiyu_Xu_, @FlamShepherd, Stephanie Kim, @NishRReddy, Shiyou Zhu, @LiliaEvgeniou, @eugene_koonin, Rhiannon Macrae.

What’s next? - Understanding TIGR’s natural function—Defense system? Genome organizer? A new function yet to be discovered? - Engineering TIGR for precision genome editing. - Exploring relationships with box C/D snoRNPs and IS110 transposases and uncovering more Nop-based

Unlike CRISPR, TIGR is PAM-free, allowing broader targeting. We demonstrated TasR-mediated genome editing in human cells, opening the door for TIGR-based tools, including RNA-guided DNA notifications, base editing, etc.

TIGR encodes structured RNA arrays in dual-repeat or stem-loop architectures, transcribed into small tigRNAs (~36 nt) with two interspaced guides. The TIGR-associated protein (Tas) is modular, acting as TasA (Nop domain) or fused to nucleases (TasR, TasH). Cryo-EM shows TasR

TIGRs encode Tandem Interspaced Guide RNA (TIGR) sequences in structured arrays. It has 2 architectures—dual-repeat arrays & stem-loop arrays – that are transcribed and processed into tigRNAs, which guide TIGR associated (Tas) effectors.

We found that a RNA binding domain of SpCas9 is structurally similar to a region of Nop domain, a known RNA-binding fold in box C/D snoRNPs and IS110 transposases. Further mining of the Nop domain revealed a previously-unknown family of RNA-guided systems in prokaryotes and

Most RNA-guided systems are found by searching for conserved nuclease domains. We took a different approach, starting from Cas9 REC domains using structural mining, Iterative searches, and LLM-based clustering.

We are excited to report the discovery of TIGRs, a widely-occurring RNA-guided system found in bacteria and their viruses. TIGRs consist of a peculiar repeat region which is transcribed into RNA and processed into multiple guide RNAs to direct TIGR-associated proteins to their

RNA-guided systems span kingdoms, from bacterial immunity to eukaryotic gene regulation. How did they evolve? We traced the origins of CRISPR-Cas13 and identified its likely ancestor: an RNA-based toxin-antitoxin (TA) system. Here’s what we uncovered: https://t.co/oTGjiN2V3H 1/8

#CRISPR revolutionized medicine, but where did its RNA-guided mechanisms come from? Using #AI, we unearthed new Cas13s and found they evolved from toxin-antitoxins, revealing how nature created these amazing reprogrammable molecules. Discover the recipe: https://t.co/nUws6DpNhD

Congratulations to @rumya_r @mircoscopy @DStrebinger @blake_lash @cyrusbiotech and colleagues on an exciting study combining AI and protein engineering to minimize the immunogenicity of Cas9 and Cas12a nucleases. These approaches have the potential to improve the safety and

Happy 2025=1^3+2^3+3^3+4^3+5^3+6^3+7^3+8^3+9^3 and many new discoveries!

Today we report Evo, a generalist foundation model for biology, on the cover of @ScienceMagazine. Trained on billions of DNA nucleotides, Evo was designed to capture two key aspects of biology: the multi-modality of the central dogma and the multi-scale nature of evolution.

Excited to see our team’s work on Fanzor now published in @CellCellPress! Amazing effort by @Peiyu_Xu_ and the entire team in uncovering the structural diversity and DNA cutting mechanisms of Fanzor. Proud of everyone involved! Onward to more discoveries. 🚀

Nature is amazing! Congratulations to @maxewilkinson and team on a beautiful study revealing a clever way that bacteria defend against viruses. Check out Max’s posts for more detail! https://t.co/McWpVBuIMz

Congratulations to all of the graduates during this commencement season! Wishing you all a creative and fulfilling future!​​​​​​​​​​​​​​​​ "What you follow with your heart will indeed come back to make your life much richer."