Single-Cell Biology & Dynamics
Developing machine learning methods to understand cellular development, state transitions, and responses to stimuli using single-cell omics data.
We develop machine learning methods to understand how cells develop, respond to stimuli, and transition between states. Our work began with TrajectoryNet, which used dynamic optimal transport to model cellular dynamics, and has since expanded to MIOFlow, a framework that integrates manifold learning, optimal transport, and neural differential equations to infer continuous trajectories from discrete single-cell snapshots.
Current research focuses on extending these methods to incorporate spatial transcriptomics data (MIOFlow 2.0), model stochastic cellular dynamics, and benchmark the growing field of single-cell analysis methods. We also apply our tools to understand disease mechanisms—including cancer cell plasticity, inflammatory processes in macular degeneration, and pancreatic adenocarcinoma progression—at single-cell resolution.
By combining generative modeling with biological domain knowledge, we aim to build computational tools that help researchers extract mechanistic insights from high-dimensional single-cell data.
Key Directions
- Cellular Trajectory Inference: Learning continuous cell state transitions using neural ODEs and optimal transport (TrajectoryNet, MIOFlow)
- Spatial Transcriptomics: Integrating single-cell and spatial data to uncover tissue-scale trajectories (MIOFlow 2.0)
- Perturbation Analysis: Quantifying cell responses to experimental treatments using graph signal processing
- Disease Mechanisms: Understanding cancer cell plasticity, inflammation, and disease progression at single-cell resolution
- Benchmarking: Defining open problems and standardized evaluation for single-cell analysis methods
Selected Publications
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MIOFlow 2.0: A Unified Framework for Inferring Cellular Stochastic Dynamics from Single Cell and Spatial Transcriptomics Data
Xingzhi Sun, João Felipe Rocha, Brett Phelan, Dhananjay Bhaskar, Guillaume Huguet, Yanlei Zhang, Alexander Tong, Ke Xu, Oluwadamilola Fasina, Mark Gerstein, Natalia Ivanova, Christine L. Chaffer, Guy Wolf, Smita Krishnaswamy
Preprint
March 2026
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Defining and Benchmarking Open Problems in Single-Cell Analysis
Malte Luecken, Scott Gigante, Daniel Burkhardt, Robrecht Cannoodt, Daniel Strobl, Nikolay Markov, Luke Zappia, Giovanni Palla, Wesley Lewis, Daniel Dimitrov, Michael Vinyard, Daniel Magruder, Alma Andersson, Emma Dann, Qian Qin, Dominik Otto, Michal Klein, Olga Botvinnik, Louise Deconinck, Kai Waldrant, Bastian Rieck, Constantin Ahlmann-Eltze, Eduardo Da Veiga Beltrame, Andrew Benz, Carmen Bravo González-Blas, Ann Chen, Benjamin DeMeo, Can Ergen, Swann Floc'hlay, Adam Gayoso, Stephanie Hicks, Yuge Ji, Vitalii Kleshchevnikov, Gioele La Manno, Maximilian Lombardo, Romain Lopez, Dario Righelli, Hirak Sarkar, Valentine Svensson, Alexander Tong, Galen Xing, Chenling Xu, Jonathan Bloom, Angela Pisco, Julio Saez-Rodriguez, Drausin Wulsin, Luca Pinello, Yvan Saeys, Fabian Theis, Smita Krishnaswamy
In Nature Biotechnology, 2025
June 2025
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Generating Multi-Modal and Multi-Attribute Single-Cell Counts with CFGen
Alessandro Palma, Till Richter, Hanyi Zhang, Manuel Lubetzki, Alexander Tong, Andrea Dittadi, Fabian Theis
In ICLR 2025
May 2025
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Hidden sampling biases inflate performance in gene regulatory network inference
Marco Stock, Florin Ratajczak, Paul Bertin, Eva Hoermanseder, Yoshua Bengio, Jason Hartford, Pascal Falter-Braun, Matthias Heinig, Alexander Tong, Antonio Scialdone
Preprint (bioRxiv)
April 2025
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Metric Flow Matching for Smooth Interpolations on the Data Manifold
Kacper Kapusniak, Peter Potaptchik, Teodora Reu, Leo Zhang, Alexander Tong, Michael Bronstein, Avishek Joey Bose, Francesco Di Giovanni
In NeurIPS 2024
December 2024
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Single-Cell Analysis Reveals Inflammatory Interactions Driving Macular Degeneration
Manik Kuchroo, Marcello DiStasio, Eric Song, Eda Calapkulu, Le Zhang, Maryam Ige, Amar H. Sheth, Abdelilah Majdoubi, Madhvi Menon, Alexander Tong, Abhinav Godavarthi, Yu Xing, Scott Gigante, Holly Steach, Jessie Huang, Guillaume Huguet, Janhavi Narain, Kisung You, George Mourgkos, Rahul M. Dhodapkar, Matthew J. Hirn, Bastian Rieck, Guy Wolf, Smita Krishnaswamy, Brian P. Hafler
In Nature Communications
June 2023
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Learning Transcriptional and Regulatory Dynamics Driving Cancer Cell Plasticity Using Neural ODE-Based Optimal Transport
Alexander Tong, Manik Kuchroo, Shabarni Gupta, Aarthi Venkat, Beatriz P. San Juan, Laura Rangel, Brandon Zhu, John G. Lock, Christine L. Chaffer, Smita Krishnaswamy
In BioRxiv
April 2023
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Manifold Interpolating Optimal-Transport Flows for Trajectory Inference
Guillaume Huguet, D. S. Magruder, Alexander Tong, Oluwadamilola Fasina, Manik Kuchroo, Guy Wolf, Smita Krishnaswamy
In NeurIPS
December 2022
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Quantifying the effect of experimental perturbations in single-cell RNA-sequencing data using graph signal processing
Daniel B. Burkhardt, Jay S. Stanley, Alexander Tong, Ana Luisa Perdigoto, Scott A. Gigante, Kevan C. Herold, Guy Wolf, Antonio J. Giraldez, David van Dijk, Smita Krishnaswamy
In Nature Biotechnology
June 2021
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TrajectoryNet: A Dynamic Optimal Transport Network for Modeling Cellular Dynamics
Alexander Tong, Jessie Huang, Guy Wolf, David van Dijk, Smita Krishnaswamy
In ICML. Also at LMRL Workshop @ NeurIPS 2019
July 2020