Michael Lin, MD PhD

Pretty much destroys Harvard's previous contention that Asian-Americans with excellent grades and extracurriculars were undeserving due to some unidentifiable deficiencies. It took 30 years (this issue was discussed when I was there) but some things do change, eventually

Cool work from former postdoc Jihye Seong's lab (at Seoul National University College of Medicine)

15h

"target" will be subject to "search & rescue" 🙄

This week feels like living in a bizarro world: Losing money is celebrated; profitability questioned. Ignorance is trusted; knowledge dismissed. Criminals are defended; victims attacked. Cowards attract followers; the courageous are shunned.

We can trace this back to a political system claiming decisions based on expertise while overseeing decades of manufacturing job losses and wage stagnation. In reality politicians' claims of using expertise have always been exaggerated, at least since I started paying attention)

But I wonder is there a term for the psychological phenomenon by which someone, after rejecting one moral standard as having harmed them, then rejects a series of other standards? I don't think this is just hasty generalization which is more about conclusions of cause and effect.

PSA: get your flu shot now if you haven't already Using last year's flu trends as a template, from today we expect infection rates to double every 1.5 weeks, peaking ~2 months from now. After vax, immunity takes 1.5 weeks to kick in, peaks at 1-2 months, decays after 3 months.

Wherein a couple of tech bros get excited that Claude can propose exactly the same things that researchers did a few years ago

nature.comDe novo designed proteins neutralize lethal snake venom toxins - NatureDeep learning methods have been used to design proteins that can neutralize the effects of three-finger toxins found in snake venom, which could lead to the development of safer and more accessible an...

And here's what was done before (lin www.nature.com/articles/s41...

Showing AI can propose me-too projects is not the win that tech bros think it is, when (1) biologists do computational protein design all the time, with or without Claude (2) biologists also do the subsequent testing steps which is what takes 99% of the time and money

The study suggests young researchers make more disruptive discoveries, and older ones fewer but more lasting ones. Perhaps experience, time, and awareness of long-term bottlenecks might be advantages for older researchers to make the more difficult and lasting breakthroughs.

Another possibility: postdocs and young PIs develop and train on the latest methods (RNAi, CRISPR, now AI), and these provide finding that can overturn earlier conclusions, so we get large bursts of disruptive work by younger researchers, but these aren't grand paradigm shifts

youtube.comTheranos fraud: Up close and personal with Elizabeth Holmes' charm and lies | 60 Minutes AustraliaYouTube video by 60 Minutes Australia

This is the clearest behind-the-scenes exposé of Theranos I've heard. TylerShultz is my hero, and a funny guy too. Per Tyler, every scientist there knew that not only did the technology and tests not work, but there was no real technology to begin with. www.youtube.com/watch?v=MsUK...

Michael Lin, MD PhD reposted

Adam Cohen (My Personal Views Only)

@axidentaliberal.bsky.social

Zuckerberg shut down No Kings on Meta Trump banned news outlets from the White House Now TikTok wants to erase the “Musk” documentary Billionaires wants to control our information, because they believe uninformed masses are compliant-and more profitable for them This will backfire Spectacularly

Alex Gibney@alexgibneyfilm.bsky.social

Note: TikTok - 15% owned by Musk pal Larry Ellison - permanently banned our "Musk" the movie account on the platform. www.hollywoodreporter.com/news/politic...

hollywoodreporter.comTikTok “Permanently Suspends” the ‘Musk’ Film Ad Account, Raising Suppression Fears (Exclusive)Move comes just as Alex Gibney doc film expands to nearly 500 screens. Distributor Bleecker Street says it is appealing.

After everything that AI has done to decimate funding for biology research (and biotech companies with actual products), it will be poetic justice when biology pops the AI bubble.

Was fun celebrating the recent Nobel with many of the pioneers in optogenetics at Optogen 2026 in beautiful Barcelona — a great place to reunite with old friends. The conference brought together wide range of approaches, from optical methods to new indicators to clinical trials

I presented ASAP voltage indicators, bioluminescent neurotransmitter reporters, and psCas12f photoswitchable gene editors... not optogenetics as defined by the Nobel committee, but still involving photons and genetic tools. Many thanks to @ibecbarcelona.eu for the invitation!

As luck would have it, my PhD advisor Mike Greenberg happened to be in Barcelona at the same time as me. Like a science-y version of a Whit Stillman movie, we chatted about engrams and enhancers while dining over tapas and strolling through the city.

A nice demonstration of how much confounding factors in cohort studies can create spurious associations To hyper-generalize, it demonstrates the fragility of association, which vary by conditions. Yet association is the main (only?) mechanism by which AI can build biology models

The joke in the 2000s was that "China" was the answer to every investing question, when in the 1990s it was "the internet". Now we have the double-whammy occurring for biotech, with the reason to not try anything new in the US being China AND computers.

Celebration at Stanford Bioengineering for Karl Deisseroth’s Nobel Prize. His commitment to teaching came up, and Karl said something very interesting: that one of the best feelings is finishing a classroom session and thinking it went well, that the students learned something. Completely agree!

Karl opined that there may be an evolutionary reason for this feeling, because we are a social species and survival depended on teaching. Now we just need to find the pathway from the cortex to the VTA for that.

cell.comNon-invasive control of gene editing in vivo by photoswitchable Cas12f and focused ultrasoundRemote activation of a single-AAV-deliverable photoswitchable Cas12f system enables precise spatial and temporal control of genome editing in deep tissues without surgery or implanted devices.

Excited to share a new study from our lab in Cell: “Non-invasive control of gene editing in vivo by photoswitchable Cas12f and focused ultrasound” We engineered a compact CRISPR system that can be activated at specific locations in the body using focused ultrasound (🧵) www.cell.com/cell/fulltex...

And would not have been possible without early support from Stanford Bio-X, the Focused Ultrasound Foundation, and the SMA Foundation, and sharing the same roof with the Hong lab at the Stanford Wu Tsai Neuroscience Institute

addgene.orgAddgene: Non-invasive control of gene editing in vivo by photoswitchable Cas12f and focused ultrasound.

24/25Plasmids available on addgene for those who'd like to try: www.addgene.org/browse/artic...

Many people to thank on this fun and intense collaborative project: Michael Westberg for ideas on designs, Yichi Su for the reporter construct; Marigold Malinow, Xiang Wu, Shan Jiang, and Sa Cai for MLNT synthesis and ultrasound experiments, Dongyun Jiang for histology...

Dongin Lee and Hanlee Ji for NGS; Nicole Repina and David Schaffer for engineering a programmable multi-well illuminator; and of course Guosong Hong for co-directing the project!

There is more to explore, e.g. cell-type-specific expression and generalizing ps-Cas12f to non-editing outputs. More broadly, we hope that remote control of engineered proteins in vivo inspires others to think of other ways in which engineering can lead to smarter medicines.

authors.elsevier.comPlease wait whilst we redirect youAll content on this site: Copyright © 2026 Elsevier B.V., its licensors, and contributors. All rights are reserved, including those for text and data mining, AI training, and similar technologies. For all open access content, the relevant licensing terms apply.

Like to full-text article, free for the first 50 days: authors.elsevier.com/a/1nr-iL7PXy...

So why is local gene editing useful? For example to treat Huntington's Disease, we'd prefer to disrupt HTT in just the striatum if possible, in case it has essential functions elsewhere. Also caging Cas12f by default reduces off-target toxicity that would otherwise accumulate.

Actually we found Cas12f variants to have less off-target activity than Cas9, replicating earlier results. So we are taking a low risk and making it even lower. IMO all future CRISPR will be Cas12f CRISPR: smaller, more specific, and just as active — and now regulatable in 4D.

So we delivered ps2-CasMINI across the BBB using AAV serotype CAP.B10 (from the Gradinaru lab), then perform local ultrasound induction of reporter gene editing at one location in the brain. (We show the pseudocolor overlays because that's standard but we like to show raw luminescence images too)

It's interesting to think about what's happening here: The MLNTs circulate in the bloodstream. The light they produce cross the BBB to activate ps-CasMINI whose genetic instructions had crossed the BBB earlier in AAV!

And so in a close collaboration with the Hong lab, we injected AAV to express ps-Cas12f in muscle, then injected mechanoluminescent nanotransducers (MLNTs), then performed ultrasound to trigger light production at the focal point and induce Cas12f-mediated gene editing.

The brain is one place where local gene editing would be useful. As neurologists know, many conditions are localized, so it would be nice if CRISPR-based genetic treatments can be local too. But location-specific promoters often don't exist, and it would be nice to avoid surgery.

And it works in vivo! We delivered each system in a single AAV to mouse legs, then applied external light Light induced luciferase transgene activation (due to gRNA-targeted editing of a stop signal in front of the luciferase) by ~19x vs no light, reaching similar activity levels as unfused CRISPR

Okay but external illumination isn't really local or deep. That's where the 2nd engineering effort comes in, in the development of mechanoluminescent nanoparticles by Guosong Hong's lab. These are particles that generate cyan light upon ultrasound stimulation, perfect for pdDronpa!

But pdDronpa's photoresponse was fairly inefficient, occurring in <1% of photon absorbance events (the other 99% producing fluorescence). Thus psCasMINI needed more photons to switch vs. natural photosensory domains, e.g. LOV or cryptochrome. And CasMINI was not as active as the standard Cas9.

We fixed this. We engineered a faster-switching pdDronpa2, then made "ps2" variants with newer higher-activity Cas12f variants, eCas12f and AsCas12f-HKRA The result was ~20x more gene editing in response to lower amounts of light, reaching the same activity as unfused Cas9.

But the cool thing is: in the Cas12f:gRNA complex, the two N-termini of Cas12f already flank the gRNA. Thus if we fuse just *1* pdDronpa domain to the Cas12f NT, the pdDronpa dimer should form across the gRNA to cage it Here's my manual model from 2021. No AF, no ML. Just PyMol.

Amazing postdoc Daesun Song took up the project. He quickly made a psCasMINI that showed ~13-fold induction of gene editing with light, and induced activity similar to unfused CasMINI. All within 2.5kB, small enough to fit, along with a gRNA gene, into a single AAV particle

cell.comEngineered miniature CRISPR-Cas system for mammalian genome regulation and editingXu et. al developed a miniature CRISPR system for genome engineering via protein and guide RNA engineering. Whereas the natural Cas12f does not function in mammalian cells, engineered Cas12f mutants, ...

The smallest CRISPR systems are the Cas12f family. Two Cas12f chains wrap around one sgRNA, allowing each to be less than 1/2 the size of the original Cas9 proteins where 1 chain wraps around 1 sgRNA. The first Cas12f variant used in mammals was CasMINI: www.cell.com/molecular-ce...

Previously, we had made single-chain photoswitchable proteins by attaching pdDronpa at 2 locations flanking an active site. The pdDronpa dimer cages the site in the dark, while light induces dissociation and uncaging Cartoon below for psMEK (red molecule is ATP in active site)

science.orgOptical control of cell signaling by single-chain photoswitchable kinasesSingle-chain photoswitchable kinases based on engineered photodissociable proteins enable fine control of kinase activity.

There were two key protein engineering steps: using our pdDronpa photodissociable GFP to control the compact CRISPR protein Cas12f with light, and improving photosensitivity of pdDronpa to make photoregulation more efficient in vivo. The 2017 paper on pdDronpa: www.science.org/doi/10.1126/...

pdDronpa is dimeric in the dark. Cyan light dissociates it into monomers. Redimerization occurs spontaneously in ~1h, or immediately with a little violet light. pdDronpa is the first (and only?) synthetic photosensory domain, and nicely doesn't require a cofactor as it's a GFP.

The challenge: Can we select not only which gene to disrupt with a CRISPR system, but also where in the body to disrupt it? If we could do this, then we can eventually control gene function in particular parts of the body (especially the nervous system) even without a specific promoter.