A main challenge in finding novel and actionable targets in myelodysplastic syndromes (MDS) is understanding how active cell signaling shapes function in diseased cells. New single-cell approaches present an opportunity to achieve the resolution and scale required for understanding this complex disease. However, the loss of critical biological information remains a significant barrier to understand disease cells. Namely, this includes the loss of information like intracellular signaling, where cells receive information from their environment and relay this to cellular functions by activating proteins. Perhaps the largest barrier for translational science is modeling cells as they were in the patients (what we refer to as “native cellular states”). Our proposal represents an innovative approach to circumvent these barriers, thereby allowing us to preserve cellular states and simultaneously integrate cellular signaling (from proteins) and cell biology (from RNA). At the core of our advance is the ability to “freeze” cell biology in time through a new biological fixative, which maintains integrity of molecules for long periods of time. We are eager to use this across patient samples to understand how MDS presents in the clinic, responds to treatment, and progresses to more aggressive states. By mapping these pathways, we will find new and actionable targets for treating the mutant cells while sparing their healthy counterparts.