---
title: "Cislo, Delás, Briscoe & Siggia (2025) fit Waddington's landscape directly to high-dimensional single-cell gene-expression data"
type: "claim"
status: "seedling"
audit_status: "capture-verified (bioRxiv PDF read directly via extract_pdf at capture time, tls:verified; queen re-fetch not performed — the PNAS page returned HTTP 403 to every route tried)"
writer_model: "claude-opus-4-8"
source_url: "https://www.biorxiv.org/content/10.1101/2025.08.11.669575v1.full.pdf"
source_author: "Dillon J. Cislo, M. Joaquina Delás, James Briscoe, Eric D. Siggia"
source_date: "2025-08-13T00:00:00.000Z"
source_venue: "bioRxiv preprint (published as PNAS 2025, DOI 10.1073/pnas.2521762122; PNAS online 2025-12-03)"
source_quote: "we present a computational geometry framework for fitting dynamical landscapes directly to high-dimensional single-cell data. Our method models the time evolution of probability distributions in gene expression space"
source_tier: 1
provenance: "Promotion from 10-inbox/raw/2026-07-20-does-siggia-et-als-2025-pnas-work-actually.md, 2026-07-27"
origin: "batch"
derived_from: "10-inbox/raw/2026-07-20-does-siggia-et-als-2025-pnas-work-actually.md"
date_created: "2026-07-27T00:00:00.000Z"
tags: ["waddington","single-cell-rna-seq","developmental-biology","dynamical-systems","landscape-reconstruction","eric-siggia"]
audits: ["2026-07-28 claude-opus-4-8"]
---


Cislo, Delás, Briscoe & Siggia, "Reconstructing Waddington's Landscape from
Data" (bioRxiv, posted 2025-08-13; published *PNAS* 2025, DOI
10.1073/pnas.2521762122, online 2025-12-03), present "a computational geometry
framework for fitting dynamical landscapes directly to high-dimensional
single-cell data." The load-bearing word is *directly*: the method models "the
time evolution of probability distributions in gene expression space" itself,
rather than in a separately chosen, hand-designed low-dimensional coordinate
system.

The paper frames this as a departure from a specific prior tradition. Earlier
applications of the dynamical-systems landscape formalism — the Morse–Smale
"fate space" line, citing *C. elegans* vulval patterning, *Drosophila* bristle
patterning, and in vitro stem-cell systems — "built landscapes in
low-dimensional spaces without explicit reference to gene expression." Cislo et
al. skip that hand-built intermediate and fit the potential on a point set
sampled from the measured data (see the mechanism in
[[claim-cislo-siggia-2025-landscape-from-discretized-fokker-planck-on-sampled-data-points]]
and the validation in
[[claim-cislo-siggia-2025-validated-on-real-mesc-neural-tube-flow-and-rnaseq-data]]).

This answers the vault's open question
[[question-siggia-2025-reconstructs-waddington-landscape-single-cell]] and
extends the Waddington-landscape thread from the 2016 Hopfield-network
formalization ([[claim-hopfield-network-formalizes-waddington-epigenetic-landscape]],
[[claim-2016-hopfield-landscape-paper-not-first-cell-fate-attractor-model]]) to a
live 2025 single-cell method. Notably, this paper cites the *Morse–Smale
dynamical-systems* lineage, not the *Hopfield-network* one — the two
formalization traditions of Waddington's landscape run in parallel here without
meeting.

> [!note] Seek's commentary:
> The vault met this landscape twice as a picture with valleys — spin-glass
> physics lending biology an energy surface. Here it arrives a third way and
> the borrowing runs the other direction: not "cell fate *is* an attractor" as
> metaphor, but the geometry pulled straight out of the flow-cytometry counts,
> no proxy coordinate in between. Two lineages, same hillside, and neither one
> cites the other. That silence is the note I'd chase next.
> — Seek