I just finished reading this beauty from the
@KleinLabHMS 🫶🫶🫶
Multistep genomics on single cells and live cultures in subnanoliter capsules. Mazelis et al, recently published Science last December.
DOI: 10.1126/science.ady7209
I first saw Ignas start working on this almost five years ago when I was at HMS. It’s unreal, and makes me very happy, to see it go all the way to a Science paper. Legend!
In this work, Ignas and team introduce a new single-cell functional genomics platform that lets you:
-keep single cells alive
-culture them over time
-run multi-step biochemical workflows on them
-then read out genome-wide signals
The big breakthrough is the capsule design. It physically holds cells (and large biomolecules) in place, while still allowing media, enzymes, and reagents to diffuse in and out. Smart idea. Huge impact.
To make this work, they built “capsules with amphiphilic gel envelopes,” or CAGEs. These magic capsules:
-retain cells and large analytes (so you don’t lose the important stuff)
-stay permeable to media, enzymes, and reagents (so complex protocols still work)
-support high-throughput processing (so you can scale to tens of thousands of samples)
This matters because most functional genomic assays require multiple sequential steps. Those workflows fall apart when you try to scale them across large numbers of living single cells. CAGEs solve that, which allowed the team to:
-run high-throughput, multi-step workflows on living single cells (not limited to “one-pot” reactions)
-create a DNA library barcoding strategy for CAGE-derived material, so you can pool capsules without losing cell identity
-measure how gene expression programs persist through clonal expansion
-link lineage-like clonal growth with transcriptome readouts at real scale
Most single-cell sequencing methods are great at snapshots. But biology is dynamic. We care about things like:
-response to stimuli
-stability of cell states
-differentiation
-expansion of rare clones
This platform tackles one of the biggest bottlenecks in the field:
Scaling live-cell, multi-step functional measurements to high throughput, while still getting genome-wide readouts!!!
Big congratulations to the entire team!
I remember seeing the very first tests in this magical work…
Amazing science from
@KleinLabHMS
Multistep genomics on single cells and live cultures in subnanoliter capsules | Science
science.org/doi/10.1126/scie…