Position: Virtual Cells Need Context, Not Just Scale

Payam Dibaeinia, Sudarshan Babu, Mei Knudson, Ali Elsheikh, Yibo Wen, Han Liu, Jason Perera, Aly A Khan
Proceedings of the 43rd International Conference on Machine Learning, PMLR 306:169981-169998, 2026.

Abstract

The intersection of AI and biology has entered a phase of explosive growth, driven by the ambition to build "Virtual Cells" or computational models capable of predicting cellular responses to any perturbation. Following the success of structural biology (e.g., AlphaFold) and large language models, the field has converged on training massive, high-capacity models on large-scale single-cell data. This position paper argues that scaling model capacity is insufficient to solve the Virtual Cell problem because the primary failure mode is a lack of adequate coverage over diverse biological contexts, not insufficient model expressivity. We support this claim by reviewing recent studies showing that simple baselines perform on par with sophisticated architectures within a given biological context, and current models fail to consistently generalize across contexts. We connect this finding to the causal inference literature on transportability and contrast it with domains where scaling has succeeded. We substantiate our argument through analysis of a state-of-the-art model on a 22-million-cell immunology dataset. We conclude that the community faces a causal transport problem that cannot be solved by accumulating more data from the same distributions. Instead, we argue that contextual diversity and causal representation learning deserve increased emphasis, complementing ongoing scaling of model capacity and data volume.

Cite this Paper

BibTeX
@InProceedings{pmlr-v306-dibaeinia26a, title = {Position: Virtual Cells Need Context, Not Just Scale}, author = {Dibaeinia, Payam and Babu, Sudarshan and Knudson, Mei and Elsheikh, Ali and Wen, Yibo and Liu, Han and Perera, Jason and Khan, Aly A}, booktitle = {Proceedings of the 43rd International Conference on Machine Learning}, pages = {169981--169998}, year = {2026}, editor = {Zhang, Tong and Dudik, Miroslav and Jaggi, Martin and Agarwal, Alekh and Li, Sharon and Schuurmans, Dale and Zhu, Jerry and Berkenkamp, Felix and Dong, Hanze and Bietti, Alberto}, volume = {306}, series = {Proceedings of Machine Learning Research}, month = {06--11 Jul}, publisher = {PMLR}, pdf = {https://raw.githubusercontent.com/mlresearch/v306/main/assets/dibaeinia26a/dibaeinia26a.pdf}, url = {https://proceedings.mlr.press/v306/dibaeinia26a.html}, abstract = {The intersection of AI and biology has entered a phase of explosive growth, driven by the ambition to build "Virtual Cells" or computational models capable of predicting cellular responses to any perturbation. Following the success of structural biology (e.g., AlphaFold) and large language models, the field has converged on training massive, high-capacity models on large-scale single-cell data. This position paper argues that scaling model capacity is insufficient to solve the Virtual Cell problem because the primary failure mode is a lack of adequate coverage over diverse biological contexts, not insufficient model expressivity. We support this claim by reviewing recent studies showing that simple baselines perform on par with sophisticated architectures within a given biological context, and current models fail to consistently generalize across contexts. We connect this finding to the causal inference literature on transportability and contrast it with domains where scaling has succeeded. We substantiate our argument through analysis of a state-of-the-art model on a 22-million-cell immunology dataset. We conclude that the community faces a causal transport problem that cannot be solved by accumulating more data from the same distributions. Instead, we argue that contextual diversity and causal representation learning deserve increased emphasis, complementing ongoing scaling of model capacity and data volume.} }
Endnote
%0 Conference Paper %T Position: Virtual Cells Need Context, Not Just Scale %A Payam Dibaeinia %A Sudarshan Babu %A Mei Knudson %A Ali Elsheikh %A Yibo Wen %A Han Liu %A Jason Perera %A Aly A Khan %B Proceedings of the 43rd International Conference on Machine Learning %C Proceedings of Machine Learning Research %D 2026 %E Tong Zhang %E Miroslav Dudik %E Martin Jaggi %E Alekh Agarwal %E Sharon Li %E Dale Schuurmans %E Jerry Zhu %E Felix Berkenkamp %E Hanze Dong %E Alberto Bietti %F pmlr-v306-dibaeinia26a %I PMLR %P 169981--169998 %U https://proceedings.mlr.press/v306/dibaeinia26a.html %V 306 %X The intersection of AI and biology has entered a phase of explosive growth, driven by the ambition to build "Virtual Cells" or computational models capable of predicting cellular responses to any perturbation. Following the success of structural biology (e.g., AlphaFold) and large language models, the field has converged on training massive, high-capacity models on large-scale single-cell data. This position paper argues that scaling model capacity is insufficient to solve the Virtual Cell problem because the primary failure mode is a lack of adequate coverage over diverse biological contexts, not insufficient model expressivity. We support this claim by reviewing recent studies showing that simple baselines perform on par with sophisticated architectures within a given biological context, and current models fail to consistently generalize across contexts. We connect this finding to the causal inference literature on transportability and contrast it with domains where scaling has succeeded. We substantiate our argument through analysis of a state-of-the-art model on a 22-million-cell immunology dataset. We conclude that the community faces a causal transport problem that cannot be solved by accumulating more data from the same distributions. Instead, we argue that contextual diversity and causal representation learning deserve increased emphasis, complementing ongoing scaling of model capacity and data volume.
APA
Dibaeinia, P., Babu, S., Knudson, M., Elsheikh, A., Wen, Y., Liu, H., Perera, J. & Khan, A.A.. (2026). Position: Virtual Cells Need Context, Not Just Scale. Proceedings of the 43rd International Conference on Machine Learning, in Proceedings of Machine Learning Research 306:169981-169998 Available from https://proceedings.mlr.press/v306/dibaeinia26a.html.

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