A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases
Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI's cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI's predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.
Authors
- Jonas C. Schupp (ORCID: https://orcid.org/0000-0002-7714-8076)
- Emanuela Elsa Cortesi (ORCID: https://orcid.org/0000-0003-1067-9179)
- Marianne Sylvia Carlon (ORCID: https://orcid.org/0000-0002-8263-0350)
- A. Justet
- Robin Vos (ORCID: https://orcid.org/0000-0002-3468-9251)
- Iván O. Rosas (ORCID: https://orcid.org/0000-0003-4622-618X)
- John E. McDonough (ORCID: https://orcid.org/0000-0003-2497-0258)
- Bart M. Vanaudenaerde (ORCID: https://orcid.org/0000-0001-6435-6901)
- Laurens De Sadeleer (ORCID: https://orcid.org/0000-0003-1237-7369)
- John Sembrat (ORCID: https://orcid.org/0000-0003-4108-803X)
- Taylor Adams (ORCID: https://orcid.org/0000-0003-4280-9070)
- Jun Ding (ORCID: https://orcid.org/0000-0001-5183-6885)
- Marie Vermant (ORCID: https://orcid.org/0000-0001-8546-8638)
- Mélanie Königshoff (ORCID: https://orcid.org/0000-0001-9414-5128)
- Xiting Yan (ORCID: https://orcid.org/0000-0001-8688-9004)
- Wim Wuyts (ORCID: https://orcid.org/0000-0001-9648-3497)
- Farida Ahangari (ORCID: https://orcid.org/0000-0002-4144-9395)
- Naftali Kaminski (ORCID: https://orcid.org/0000-0001-5917-4601)
- Gérémy Clair (ORCID: https://orcid.org/0000-0003-0478-8520)
- Yumin Zheng (ORCID: https://orcid.org/0009-0008-4580-5247)
- Ricardo Pineda (ORCID: https://orcid.org/0000-0001-8768-4801)
- Paul Hansen
Institutions
- Pacific Northwest National Laboratory (US)
- University of Pittsburgh (US)
- Baylor College of Medicine (US)
- McGill University Health Centre (CA)
- Yale University (US)
- Medizinische Hochschule Hannover (DE)
- German Center for Lung Research (DE)
- Mila - Quebec Artificial Intelligence Institute (CA)
- McGill University (CA)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Biomedical Engineering
- Published
- 2025-06-20
- DOI
- https://doi.org/10.1038/s41551-025-01423-7
- Citations
- 13
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- U.S. Department of Defense
- Fondation du Souffle
- Three Lakes Foundation
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- National Institutes of Health
- Fonds de Recherche du Québec-Société et Culture
- Canadian Institutes of Health Research