STC: Center for Genome Intelligence Engineering (GENIE)

Every cell in the human body shares the same genetic code, yet a heart cell functions entirely differently than a brain cell. While the genetic code provides the basic instructions, cells rely on a second, physical code to know which instructions to use. This code is written in the 3-dimensional (3D) shape of the two meters of DNA folded inside each micron-sized cell. Because this 3D DNA network actively learns and calculates how a cell should respond to its environment, it acts like a biological computer. The Center for Genome Intelligence Engineering (GENIE) is launching a fundamentally new field of science to master this Genome Intelligence. Over a human lifespan, this physical architecture breaks down, causing cells to "forget" their healthy functions—a root cause of Alzheimer's, heart failure, cancer, and aging. Making radical advances in human health requires harnessing Genome Intelligence. By treating cellular decline as an engineering challenge rather than an inevitable decay, GENIE will develop technologies that physically reshape DNA folding to help tissues resist injury, recover lost function, and regenerate. Mastering Genome Intelligence requires converging physics, biology, computing, and engineering; therefore, GENIE unites a coalition of researchers across eight U.S. universities. As part of its broader impacts, the Center will train the next generation of innovators by launching a graduate program in Genome Intelligence and creating scalable research pathways for students from non-research-intensive universities in both urban and rural communities. The ultimate goal is for GENIE's discoveries to transform human health by extending the healthy years of life for millions. To achieve this goal, GENIE will decode the principles of cellular transcriptional memory (a cell's ability to maintain identity and respond to stimuli) physically encoded in the 3D genome geometry. GENIE builds upon the discovery that the genome functions as a physical Genome Geometry Network (GGN), a biological learning system that computes and strengthens useful structural configurations. To enable predictable engineering of cell fate, GENIE converges physics, biology, artificial intelligence (AI), and engineering across three integrated Science and Technology Thrusts. The Foundational Science Thrust will uncover the physical and computational rules governing the GGN and its reinforcement learning. These discoveries will be driven by the Enabling Technologies Thrust, which will develop multiscale molecular modeling, AI-powered omics, and nanoscale-imaging to map genome geometry from atomistic details to cell populations. These insights will power the Chromatin Engineering Thrust to write and erase cellular memory by manipulating three physical forces shaping genome geometry: chemical adhesion via Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based synthetic domain architecting, electrostatic via frequency-encoded electromagnetic modulation, and mechanical via morphomodulatory biomaterials. These technologies will be deployed across three Crosscutting Testbeds: programming cellular resilience to ischemia, rejuvenating neurons in Alzheimer’s disease models, and regenerating post-mitotic cardiomyocytes and neurons to combat aging. By establishing a physics-guided framework measured by biological function endpoints, GENIE will lay the foundation for Genome Intelligence Engineering to drive future radical advances in human health outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.