The Advanced Research Projects Agency for Health (ARPA-H) has awarded contract in the Critical Illness Immunological Reprogramming and Control Point Learning Engine (CIRCLE) program, which seeks to reimagine the way clinicians care for the 4.6 million Americans admitted to intensive care units (ICUs) each year. 

Among patients who make it out of intensive care, many struggle with long-term complications such as post-ICU syndrome, a collection of debilitating physical and cognitive symptoms that can persist for months or years after discharge. The research teams will build and test tools that give hospital care teams a real-time window into a patient's immune system, so they can intervene sooner and prevent both immediate death and lasting complications. 

“Because major injuries and infections usually happen without warning, every one of us is at risk of critical illness. When patients arrive in the ICU, they bring unique biology to care teams that have limited tools to understand how dangerous underlying immune dysregulation is affecting the body and few opportunities to individualize treatment,” said CIRCLE Program Manager Yoram Vodovotz, Ph.D., in a statement. “The critical care field is overdue for an infusion of technology that can illuminate that level of biological detail and give each individual patient the best chance at survival and long-term health. Through CIRCLE, ARPA-H is stepping in to catalyze that innovation and build the tools ICU teams need today to save lives.” 

The agency’s commitment is up to $144.9 million over five years.

CIRCLE aims to empower care teams with real-time monitoring and response tools that guide them toward the most effective immunotherapies for individual patients. This will include AI-powered “digital twins” of patients’ immune systems that can model strategies to address dangerous immuno-inflammation and interrupt the cascade toward organ failure before it starts.  

Each Technical Area performer in CIRCLE will strive to meet the program goals of delivering a 25% reduction in length of ICU stay for critically ill patients through the development of an integrated system for measuring components of the patient’s immune system, modeling the immune system state with digital twins, determining actionable immune system control points, and modulating those control points to improve patient health.   

The selected teams are led by: 
• University of Vermont. This team will monitor multiple immune mediators, immune cell function, and neurophysiological state. These data, along with electronic medical records, will inform an enhanced digital twin based on computational models that simulate potential novel therapies approved by the U.S. Food and Drug Administration (FDA) in the context of individual patients at the immune-cellular level.
• Stanford University. This team will assay a wide range of transcriptomic immune system and organ-specific markers. These data as well as electronic medical records will inform a multi-modal mechanistic digital twin that explicitly models the organs affected by critical illness and propose FDA-approved therapeutics. Validation of model predictions will use an innovative, multi-organoid “assembloid” platform. 
• Novelna Inc. This team will develop a dual-channel, multi-plex sensor to deliver high-frequency, tissue-localizable immune measurements. These data will inform an ensemble digital twin incorporating multiple mechanistic model structures to identify and rank potential control points in the context of potential FDA-approved and novel therapeutic interventions. 

The Vanderbilt-led effort is called the Goldilocks Program, for Groundbreaking Organization Leveraging Data Insights: Learning for Optimized Critical care Knowledge and Systems. If successful, it will help move critical care toward a predictive, precision-based field that identifies and corrects dangerous immune system dysregulation before irreversible organ injury occurs.

“CIRCLE represents an unprecedented opportunity to fundamentally change how we understand, monitor and treat critical illness,” said Wesley Self, M.D., M.P.H., senior vice president for clinical research at Vanderbilt Health, in a statement. “Our role is to ensure that promising innovations can move efficiently from development into clinical testing, generating the high-quality evidence necessary for adoption in real-world ICUs and ultimately improving outcomes for patients nationwide.”