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We are honored to have such a terrific write up about this work Ben! You and Caitlin did a fantastic job contextualizing and distilling @zjmaggiexu.bsky.social 's work -- thanks so much for the time and energy you folks put into this !!

Thanks Thibaut -- we're really excited about how it turned out!

Ben this was so great! Single-celled predators, cannibals, archers, ... all so hot right now 🤘

Check out the video playlist for more insight into their story and to see high-resolution views of these amazing systems at work www.youtube.com/watch?v=Gtd1...

Movie S1YouTube video by Scott Coylewww.youtube.com

@zjmaggiexu.bsky.social loved the parallels between these synthetic patterns and the ciliate architectures she loves. She joined the team and developed quantitative pipelines that allowed us to extract the frequency-dependent transitions at play. She and Eden were a dream team for this work!

This project was the brainchild of my brilliant graduate student @edenchang.bsky.social , who worked tirelessly to develop and explore this fascinating composite landscape. He is now a post-doc in Michael Rosen’s group continuing to explore exciting frontiers in condensate biology. So proud of him!

RIPPLE thus provides a non-equilibrium molecular multitool for understanding and engineering protein condensation out of equilibrium, and for exploring the spectrum of subcellular architectures that can arise when reaction-diffusion signaling and phase separation intersect.

The logic of reaction-diffusion-condensation seems general. RDC may act locally to regulate individual structures, like the T-cell synapse or transcriptional hubs; or coordinate globally to pattern whole architectures, like carboxysomes (a la @cellforganized.bsky.social) and protist ciliary arrays.

To gain intuition for these behaviors, we developed and share a RIPPLE-lab RDC webGL explorer that incorporates different condensation-dependent effects into a classic Gray-Scott Reaction-diffusion model.

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Importantly, RIPPLE reaction-diffusion-condensation architectures are not end-point structures. They can act as a scaffold for the recruitment of other macromolecules to expand their structure or functional capability.

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By screening a 6x6 combinatorial library of IDR sequences with RIPPLE, we generated dynamic IDR fingerprints that captures kinetic condensation constraints and miscibility effects relevant to the out-of-equilibrium, multi-phase context of living cells.

Surprisingly, dual-IDR targeting causes a tug-of-war between co-existing phase-separated wave regions. Depending on IDR sequence, miscibility, and connection point, this can favor formation of compositionally complex dynamic emulsions; or reinforcement of persistent sub-cellular architectures.

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By systematically varying the underlying RD waveform, we reveal frequency-dependent transitions regulating dilute, condensed, and aggregated states specified by IDR sequence chemistry. The RD wave provides a control knob for tuning to a specific structural outcome across the spectrum of forms.

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Analyzing 1000s of RIPPLE configurations showed targeting IDRs to the assembling edge of a RD-wave causes condensation of the wavefront; while targeting IDRs to the trailing edge causes droplet assembly in the wake and higher-order organization into droplet-lattices, patterns, and macrostructures.

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Fusing IDRs to the RD Activator MinE, its partner ATPase MinD, or both, generates a vast array of activity-driven condensate behaviors and self-organizing subcellular architectures—ranging from oscillating droplet networks to persistent phase-separated macrostructures that pattern the cell.

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RIPPLE leverages our adaptation of the MinDE system as a programmable reaction-diffusion (RD) system in human cells. Coupling intrinsically disordered region (IDR) condensate-forming sequences to the MinDE machinery links phase separation to an ATP-driven, pattern-forming RD network.

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Reaction-diffusion signaling creates local concentration gradients that protein condensates can react to. We systematically map this composite landscape at scale in cells using RIPPLE, a synthetic system that tethers condensate-forming IDR modules to a programmable reaction-diffusion (RD) circuit.