Cellular alchemy How solving the epigenome will let us create every healthy cell in the body

Link: cellularalchemy.substack.com/p/cellular-a...

What do you do when grants are cancelled, faculty searches are frozen, and the ability to do the science you believe in is slipping out of reach?

I wrote an essay. On efforts to solve aging with reprogramming, the primacy of the epigenome, and the path to rewriting our future:

maybe we just need more positive visions of what the future could look like if we develop mirror life

nothing cooler than watching a friend literally turn science fiction into reality

it's been awe-inspiring to watch @andrewcpayne.bsky.social and co build E11 Bio and prove that the FRO model can produce amazing, unique science

also expansion + molecular barcoding <3

Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay Tay et al. demonstrate an antigen-specific assay producing exhausted T cells that reflect those found in human tumors. They identify IKZF1 (IKAROS) as a driver of exhaustion progression and validate t...

Excited to see our T-cell exhaustion preprint published! This work is led by Tristan Tay and collaborators at AstraZeneca. See the sub-thread (reformatted for bluesky) originally composed and posted by the newly minted Dr. Tay

www.cell.com/cell-reports...

to be fair, it's been quite important to genome assembly and related areas for some time, but I think we're just scratching the surface with functional, multi-modal, and temporal readouts

combined with the speed and low cost, there's a lot of potential for both diagnostic and screening tech imo

The single-molecule accessibility landscape of newly replicated mammalian chromatin By developing a long-read sequencing method to simultaneously map replication status and protein-DNA contacts in cells, Ostrowski, Yang, et al. show that newly replicated chromatin is enriched for unw...

to shy posters, a reminder that you can literally just post about science you think is cool

& if you're looking for the next single-cell or spatial, I suspect single-molecule sequencing is about to blow up 👀
www.cell.com/cell/fulltex...
www.biorxiv.org/content/10.1...
www.nature.com/articles/s41...

just a pic of my dog maple taking "be one with nature" a little too literally

my friend Sai is a co-corresponding on this, so I suspect that's his doing!

critics normally complain single-cell atlases don't have any real biology, now they also gonna complain when it's too interventional, there's no winning I guess 😛

when you temporarily have more followers than your PI

(anyway @jbuenrostro.bsky.social is here now)

@skeetstats.xyz !optin

Happy to provide more info if needed! And thanks for pointing out the omission, we'll definitely add it to our methods section

"Inconvenient truths don't actually motivate people as much as convenient solutions. That’s what we should be seeking — and those solutions tend to be synthetic, and probably biological." – George Church, Ph.D. on The Climate Biotech Podcast

New episode! This time on The Climate Biotech Podcast, Homeworld Collective co-founders Dan Goodwin and Paul Reginato sit down with the legendary George Church—a pioneer in genomics and synthetic biology.

Spotify: open.spotify.com/episode/6LfF...
Apple Podcasts: podcasts.apple.com/us/podcast/e...

Thanks! We add an oligo with an acrydite group to link it to the gel during polymerization, then use a complementary fluorescent oligo for visualization

who knew it would be easier to get everyone to switch social media platforms than getting them to use hg38

Leonid Mirny and I wrote this for all interested in chromosomes: "The chromosome folding problem and how cells solve it"

www.cell.com/action/showP...

Human skin rejuvenation via mRNA Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induce...

wake up babe, new george church skincare routine just dropped

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

seems like a fun game for all the scientists excited by the move but also mourning having to rebuild their following (it me)

I once made a meme to explain all of the drama surrounding the word "epigenetics" - to my horror, it is now used in at least several PhD classes

Multiplexed expansion revealing for imaging multiprotein nanostructures in healthy and diseased brain - Nature Communications Mapping the nature of multiprotein nanostructures in cellular contexts remains challenging. Here, Kang and Schroeder et al. report multiplexed expansion revealing, a technique which expands proteins a...

Just published: "Multiplexed expansion revealing for imaging multiprotein nanostructures in healthy and diseased brain", led by Jinyoung Kang and Margaret Schroeder! multiExR enables antibody staining of >20 proteins in a sample w/registration error down to 25 nm. www.nature.com/articles/s41...

Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression Microscopy and genomics are both used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. While emerging multiplex...

We then show these changes are found within tissues and during aging. To learn more, check out our preprint! www.biorxiv.org/content/10.1...

Thank you to all co-authors, the Buenrostro lab, and everyone at Harvard SCRB and the Broad Institute who made this work possible!

To show the power of this approach, we applied ExIGS to progeria cells with nuclear lamina abnormalities

By combining expansion and 3D genome sequencing in the same nucleus, we can literally see how the abnormal lamin topology changes the structure of chromosomes

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In situ sequencing measures the 3D location and genomic position of each DNA fragment, letting us trace the path of every chromosome in the nucleus

We also do expansion IF imaging to measure which fragments co-localize with protein landmarks

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Expanding the genome evenly is hard because DNA is a polymer, so here we use the Buenrostro lab's favorite enzyme Tn5 to make fragments beforehand

We then do Illumina sequencing, but instead of on a flowcell, all enzymatics are performed ~inside~ the expanded nucleus

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Fortunately, we had Fei Chen & Ed Boyden, the inventors of expansion microscopy on board!

In ExM, samples are physically enlarged in gels, allowing superresolution imaging without fancy microscopes

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In situ genome sequencing resolves DNA sequence and structure in intact biological samples A technical approach allows simultaneous sequencing and imaging of genomes in human fibroblasts and early mouse embryos.

In 2020, we (Andrew Payne, Paul Reginato) showed in situ genome sequencing, which we used to reveal the 3D genome at the very first stages of life: www.science.org/doi/10.1126/...

However, the resolution of IGS is capped by nuclear volume and the diffraction limit of light

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7 years ago, I met a junior fellow named Jason Buenrostro who blew me away with a vision of futuristic genomic technologies

Today, we (Ajay Labade, Caroline Comenho) are excited to share our first steps into that future: Expansion in situ genome sequencing

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