In a groundbreaking advancement poised to redefine our understanding of biological development, researchers at Harvard’s John A. Paulson School of Engineering and Applied Sciences have unveiled a computational framework that translates the enigmatic language of cellular self-organization into a solvable optimization problem. This innovative approach harnesses the power of machine learning, specifically the technique of automatic differentiation, to decode the genetic and biochemical instructions that govern how cells grow, signal, and organize themselves into complex shapes such as organs, wings, and limbs. By reframing cellular morphogenesis as a computational challenge, scientists are now equipped with tools that could ultimately allow precise engineering of living tissues, a milestone with profound implications in regenerative medicine and bioengineering.
The process through which cells spontaneously arrange themselves into functional clusters has intrigued biologists for decades. At the heart of this phenomenon lies an intricate ballet of gene expression, signal diffusion, and mechanical forces. Until now, efforts to predict or manipulate this choreography relied heavily on laborious trial-and-error experiments, often yielding inconsistent or unpredictable results. The Harvard team’s approach circumvents this limitation by positing that the collective behavior of cells can be captured through mathematical models, where the parameters defining genetic networks and signal responses are tuned via optimization algorithms.
Central to this methodology is automatic differentiation, a computational technique initially developed to train deep neural networks by accurately and efficiently calculating gradients of complex functions. The novel application of automatic differentiation in this biological context allows researchers to assess how infinitesimal changes in any component of a gene regulatory network influence the emergent behavior of an entire tissue. This sensitivity analysis enables the discovery of “rules” or pathways that cells must follow to achieve a desired morphological outcome, effectively opening a reverse-engineering route in developmental biology.
To test and demonstrate their framework, the researchers constructed simulations embodying clusters of cells categorized into two archetypes: source cells and proliferating cells. Source cells, marked in red in their schematic visualizations, act as stationary emitters of growth factors. Proliferating cells, depicted in gray, respond dynamically to these chemical cues by dividing at rates modulated by the concentration gradients of the secreted molecules. Through iterative computational learning, the system optimized its gene regulatory parameters to achieve horizontal elongation of the cell cluster, a controlled morphogenetic behavior that echoes natural developmental processes.
Delving deeper, the learned gene network revealed an elegant regulatory motif. The receptor gene expressed by the proliferating cells activates only upon sensing the external growth factor emitted by source cells. Once activated, this receptor gene suppresses the cell division propensity, effectively concentrating proliferative activity toward the extremities of the cluster. This precise spatial control of division underpins the emergent shape, demonstrating how gene network dynamics intertwine with chemical gradients to orchestrate tissue architecture.
Such integrative modeling offers unprecedented opportunities for predictive bioengineering. Instead of manually tweaking genes or signaling molecules to guess their effects on tissue shape, scientists can now deploy computational pipelines to simulate and invert developmental scenarios. For example, one might specify a desired outcome—be it a spheroid with distinct proliferative zones or an elongated cellular formation—and let the algorithm determine the requisite genetic and biochemical parameters to induce such form. This paradigm shift could accelerate the design of artificial organs, optimize stem cell cultures, or even provide insights into pathological growth patterns such as tumors.
The implications extend beyond biological shape control. By combining physics-based models—accounting for cellular adhesion, mechanical tension, and chemical diffusion—with differentiable programming, the researchers provide a scalable approach to complex multicellular systems. This holistic perspective acknowledges that cellular behavior emerges not only from internal gene networks but also from the interplay with surrounding cells and environmental cues. Consequently, this framework lays foundational groundwork for systems biology, where computational tools unify molecular, biophysical, and mechanical factors driving morphogenesis.
Graduate student Ramya Deshpande, co-leading the study, emphasized the collaborative potential between computation and experimentation. As predictive models mature and integrate empirical data, biological experiments can shift from exploratory to hypothesis-driven workflows. Researchers might, for instance, synthesize cells with genetically encoded circuits prescribed by the algorithm, then observe real-world formation patterns to validate and refine the computational predictions. This cyclic interplay could substantially reduce the time to engineer functional tissues with predefined architectures.
Postdoctoral investigator Francesco Mottes highlighted the role of automatic differentiation in scaling these models. Traditional systems biology approaches often encounter computational bottlenecks when handling high-dimensional gene networks and cellular interactions. Automatic differentiation, with its efficient gradient computation capabilities, overcomes these challenges, enabling routine optimization of intricate biological systems. Mottes envisions that as models become both predictive and experimentally calibrated, they may drive a future where growing complex organs in vitro becomes a practical reality rather than science fiction.
The study’s innovative use of differentiable programming in biological morphogenesis also resonates with broader trends in computational bioengineering. By integrating mathematical biology, applied physics, and artificial intelligence, the framework exemplifies an interdisciplinary fusion vital for tackling life’s complexities. Researchers across developmental biology, synthetic biology, and tissue engineering stand to benefit from these advances, which democratize access to sophisticated simulation and design tools once limited to computer science domains.
Importantly, the research is not just a theoretical exercise but is aligned with experimental feasibility. The authors detail simulation results showing how source cells producing a consistent chemical gradient influence spatial patterns of proliferation, mimicking processes observed in vivo. The capability to modulate division propensities spatially lays the groundwork for engineering morphogenetic fields, potentially controlling not only shape but also function by dictating cellular differentiation zones.
The study, published in Nature Computational Science, represents a significant stride toward transforming how scientists understand and manipulate life’s architectural blueprint. Supported by agencies such as the Office of Naval Research and the NSF AI Institute of Dynamic Systems, this collaborative effort unites computational ingenuity with biological insight. The dedication of the paper to former Harvard postdoc Alma Dal Co honors the contributions of researchers advancing this frontier.
Looking ahead, the research community anticipates that such computational frameworks will evolve to incorporate richer cell types, signaling pathways, and mechanical interactions. As experimental data increasingly feeds into machine learning pipelines, the predictive control of developmental systems inches closer to reality. The dream of programming cells to self-assemble into tissues or organs with custom features now seems achievable within the coming decades, ushering in a new era of precision bioengineering driven by differentiable programming.
Subject of Research: Cells
Article Title: Engineering morphogenesis of cell clusters with differentiable programming
News Publication Date: 13-Aug-2025
Web References:
https://www.nature.com/articles/s43588-025-00851-4
http://dx.doi.org/10.1038/s43588-025-00851-4
Image Credits: Brenner group / Harvard SEAS
Keywords: Artificial intelligence, Computer modeling, Computer simulation, Engineering, Systems biology, Cell biology, Computational biology, Mathematical biology, Developmental biology, Applied physics, Mathematical physics, Statistical physics
