Kristina Ulicna

Emmanuel Noutahi, Jason Hartford, Prudencio Tossou et al.

Drug discovery is fundamentally a process of inferring the effects of treatments on patients, and would therefore benefit immensely from computational models that can reliably simulate patient responses, enabling researchers to generate and test large numbers of therapeutic hypotheses safely and economically before initiating costly clinical trials. Even a more specific model that predicts the functional response of cells to a wide range of perturbations would be tremendously valuable for discovering safe and effective treatments that successfully translate to the clinic. Creating such virtual cells has long been a goal of the computational research community that unfortunately remains unachieved given the daunting complexity and scale of cellular biology. Nevertheless, recent advances in AI, computing power, lab automation, and high-throughput cellular profiling provide new opportunities for reaching this goal. In this perspective, we present a vision for developing and evaluating virtual cells that builds on our experience at Recursion. We argue that in order to be a useful tool to discover novel biology, virtual cells must accurately predict the functional response of a cell to perturbations and explain how the predicted response is a consequence of modifications to key biomolecular interactions. We then introduce key principles for designing therapeutically-relevant virtual cells, describe a lab-in-the-loop approach for generating novel insights with them, and advocate for biologically-grounded benchmarks to guide virtual cell development. Finally, we make the case that our approach to virtual cells provides a useful framework for building other models at higher levels of organization, including virtual patients. We hope that these directions prove useful to the research community in developing virtual models optimized for positive impact on drug discovery outcomes.

Konstantin Donhauser, Kristina Ulicna, Gemma Elyse Moran et al.

Sparse dictionary learning (DL) has emerged as a powerful approach to extract semantically meaningful concepts from the internals of large language models (LLMs) trained mainly in the text domain. In this work, we explore whether DL can extract meaningful concepts from less human-interpretable scientific data, such as vision foundation models trained on cell microscopy images, where limited prior knowledge exists about which high-level concepts should arise. We propose a novel combination of a sparse DL algorithm, Iterative Codebook Feature Learning (ICFL), with a PCA whitening pre-processing step derived from control data. Using this combined approach, we successfully retrieve biologically meaningful concepts, such as cell types and genetic perturbations. Moreover, we demonstrate how our method reveals subtle morphological changes arising from human-interpretable interventions, offering a promising new direction for scientific discovery via mechanistic interpretability in bioimaging.