Theory 01/Cell state transitions/Single-cell sequencing
Transitions Are Sequential, Not Switched
A cell passing from one state to another must traverse intermediate states whose number is set by the ratio of transition time to transcriptional response time, so fast transitions appear as jumps only because the intermediates are rare.
01Mechanism
Each state requires a new transcriptional programme; traversing many programmes takes time proportional to their number, and the population samples the path unevenly.
02Prediction
Intermediate abundance should scale inversely with transition speed.
03Refutation
Bimodal populations with no intermediates at high sampling depth would remove the sequential picture.
04What makes it checkable
Single-cell sequencing of millions of cells now resolves the intermediates directly, and RNA velocity orders them. If intermediates exist at the predicted frequencies, they will appear as a ridge rather than a gap in the manifold.
05Why it was not testable before
Until cells could be measured individually, a transition was an average over a population and the intermediates were invisible.