John Doench

Drs. Matthew Meyerson and Heidi Greulich from the @broadinstitute.org sit down and discuss how they and Bayer scientists developed the first FDA-approved #CancerDrug to come from a Broad scientific discovery.

🤝 Learn more about their academic-industry alliance: https://bit.ly/4ruQNRl

Magnolia's Cafe on Rochester's deep blue Park Ave might seem like a strange place to meet Trump supporters. But over the clank of metal spoons against bowls of tomato soup, you can hear whispers that the president's friendly meeting with Mamdani may be the beginning of a pivot to the center.

blog.addgene.org A Tour of Addgene's Most Popular Pooled Libraries

Thank the @johndoench.bsky.social and Root labs for depositing these deliciously named libraries, and check out our blog post for more:

FPbase Fluorescence Spectra Viewer An interactive fluorescence spectra viewer to evaluate the spectral properties of fluorescent proteins, organic dyes, filters, and detectors.

The FPbase spectra viewer just had it's biggest software refactor in 6 years. It *should* be largely invisible to the end user (hopefully just faster and less buggy). Please let me know if you find any issues as you use it!

www.fpbase.org/spectra/

First 🟦 post - my main postdoc work is out in the world! We designed a Cas12a-based genetic screen to identify host factors that contribute to infection by the tickborne pathogen Rickettsia parkeri, and stumbled across a really exciting direct interaction between host and bacterium🦠. Check it out!

Nature suggests you use their "Manuscript Adviser" bot to get advice before submitting

I uploaded the classic Watson & Crick paper about DNA structure, and the Adviser had this to say about one of the greatest paper endings of the century:

ICE Agent, 7-Year-Old Both Wearing Same ‘Military Commando’ Halloween Costume

ICE Agent, 7-Year-Old Both Wearing Same ‘Military Commando’ Halloween Costume

When I explain that boycotting an election over an issue has never once forced a politician to embrace that issue, I'm not "scolding people to vote." I'm explaining reality.

Feel free to sit on your ass! Just don't pretend that your lazy apathy is somehow going to advance your agenda.

An illustrated map of Jamaica Plain Open Streets on Centre Street from Lamartine St. to South St from 10:30 a.m. - 3 p.m.

Enjoy car-free small business shopping, music, games, bicycling, community tabling, and more in Jamaica Plain this weekend!

📍 : Centre Street from Lamartine St. to South St. in JP
⏰: This Sunday, November 2 from 10:30 a.m. to 3 p.m.

More info: boston.gov/open-streets

Vance Flexes the Marines’ Might as Thousand Protest Trump’s Agenda VP JD Vance’s trips o a military base in California illustrated rising tensions between the federal government and Democratic leaders

This is quite a hed/subhed.
1) Start with Vance. Use strong action verb. Accept the autocratic premise that the “Marines’ Might” are Vance’s to flex.
2) Mention the protest second and absurdly describe them as in the thousands
3) Treat Trump’s strong man use of the military as a partisan scuffle.

Remember, brown 13-year-olds are hardened menaces to society, but 30-something Republican Hitler afficionados in positions of power are just li’l guys.

new at addgene

New CRISPR libraries from the @johndoench.bsky.social and Root labs — Jacquere (human) and Julianna (mouse).
A perfect pairing for your next screen. 🍷🧀
https://twp.ai/9PX2kT
https://twp.ai/4irnYP

I have lived and worked in and around Chicago for 27 years and I have been assaulted less often than Sen Paul has been in his own back yard.

79. American citizen.

I'm sorry, what?

Now with comments... Lots of comments

(A long thread)

1/n

The New York Times piece today about US science is terrible and wrong—in many ways.

I could write a whole article about this, but as one example:

“To close observers, the original crisis began well before any of this…”
No. I’m a close observer of science, and this is incorrect.

this is the exact first thing that popped into my head as well :)

Let’s be clear about what happened to Jimmy Kimmel Trump’s most brazen attack on free speech yet.

After years of complaining about cancel culture, the current administration has taken it to a new and dangerous level by routinely threatening regulatory action against media companies unless they muzzle or fire reporters and commentators it doesn’t like.

Fox News' Brian Kilmeade apologizes for saying mentally ill homeless people should be executed Brian Kilmeade suggested to "just kill" mentally ill homeless people who don't accept services offered to them.

After a co-host suggested that mentally ill homeless people who don't accept services offered to them should be jailed, Brian Kilmeade replied, "Or involuntary lethal injection, or something. Just kill 'em." on.nbcboston.com/JlG99ke

A deep dive into the destruction of US cancer research by @jonathanmahler.bsky.social “It’s an absolutely unmitigated disaster,” a former top official at NIH told him. “It will take decades to recover from this, if we ever do.” Gift link: nyti.ms/48iH3Cr

Nice work Ben!

Treatment of a severe vascular disease using a bespoke CRISPR–Cas9 base editor in mice - Nature Biomedical Engineering Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth ...

Optimization of a bespoke base editor to treat a severe pediatric vascular disease! 🫀🧬
Our manuscript describes:
1️⃣ Engineering a target-specific BE🧬
2⃣ A *must avoid* bystander edit that occurs with WT SpCas9 BEs! 🙅‍♂️
3⃣ Extension of lifespan after in vivo editing! 🐁✅

www.nature.com/articles/s41...

Hmm, not sure how to achieve (1) without just not targeting genes in those region of the genome that are prone to low-level chromosomal loss. In other words, seems unlikely that *some* successful guides targeting gene X would lead to this while others would not, right?

Yup, chromatin can inhibit Cas protein access.

But when a gene is transcribed, or DNA is replicated, chromatin is removed, so Cas proteins have a chance to find their target site.

And, if your gene of interest is never accessible (on) in a cell model, no particular reason to need to knock it out!

Best for last, the project was led by the incomparable Laura Drepanos, a computationalist in GPP (who, fun fact, will be applying to grad school this fall). I've not seen a more methodical and comprehensive analysis, or read a better first-draft of a manuscript.

I ❤️ this paper.

Happy screening!

A more points to wrap things up:
• We also provide the designs for a new mouse library, Julianna
• This new guide selection screen is implemented in CRISPick for Cas9 knockout (off-target for CRISPRi is a another story, stay tuned!)
• Libraries are on their way to @addgene.bsky.social

We conclude with a comparison of analysis methods, including a cautionary tale of false positives arising from the use of MAGeCK RRA.

We provide suggestions to "mitigate the reporting of false discoveries that, if left unchecked, would undermine confidence in large-scale perturbational screens."

We next screened this library and assessed performance via separation of essential and non-essential genes - we see much greater depletion of the former while the distribution of the latter barely budges. So we accomplished our goal: smarter picking of guides increased on-target activity.