ARPA-H selects teams to transform critical care with new lifesaving technology 

Performers in the CIRCLE program will develop and test computational tools powered by artificial intelligence (AI) to better track and intervene on patients’ immune responses in intensive care units

The Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services, today announced the teams receiving contract awards in the Critical Illness Immunological Reprogramming and Control Point Learning Engine (CIRCLE) program. CIRCLE aims to reimagine the way clinicians care for the 4.6 million Americans admitted to intensive care units (ICUs) each year. Among those 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 selected 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. 

Whether caused by a major injury, infection, or serious complication of a chronic disease, critical illness is complex and evolves quickly. Patients’ immune systems frequently swing from overactive to underactive in the time a traditional lab test is still being processed. Without the ability to see these changes as they happen, ICU care teams typically treat immune-related organ damage only after it occurs with broad, infrequent interventions.  

Without more precise care, as many as 30% of ICU patients die in the hospital. Among those who survive, many are discharged with post-ICU syndrome and other lasting complications associated with long-term elevated mortality risk. Post-ICU syndrome can look very different across patients but often involves a combination of cognitive problems (confusion, poor concentration, forgetfulness), physical symptoms (fatigue, shortness of breath, and muscle weakness), and emotional responses to trauma. While rehabilitation can help manage symptoms and recover abilities, many patients live with serious impairments for months or years. 

“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. “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.” 

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 utilize 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. 

CIRCLE has also awarded contracts to three “Acceleration Platform” performers that will both aid and evaluate the Technical Area performers. These teams will be led by: 

• Verily Health, Inc. This team will provide a CIRCLE program database for performer use that will draw in public and private critical illness datasets, as well as data generated by performers through the course of the program. These data will be utilized for performer model training and validation. The team will also generate innovative data products that will allow sophisticated search and data analysis that are intended to become resources for the broader critical care community. 
• Sage Bionetworks. This team will provide a “sandbox” digital twin development, validation, and testing environment for CIRCLE performers to use as they evolve and integrate their digital twins. With the ability to enable simulated clinical trials and incorporate synthetic data generated from large-scale computational simulations, the team will enhance the productivity of each Technical Area performer. This component will also facilitate readiness for future FDA digital twin and Software as a Medical Device (SaMD) applications. 
• Vanderbilt University Medical Center. This team will facilitate adaptive clinical trials of CIRCLE Technical Area performers’ digital-twin-guided immune modulatory therapeutic protocols to treat critically ill patients through their extensive network of partners and trial sites. Additionally, they will evaluate the acceptability and usability of all Technical Area performers’ devices and software in real-world ICUs. 

The agency’s commitment is up to $144.9 million over five years. Performer awards vary in funding amount per awardee and are contingent upon each team meeting aggressive and accelerated research milestones. If successful, CIRCLE will give critical care teams unprecedented, real-time control of patients' immune systems—helping prevent organ-damaging inflammation, save lives in the ICU, and protect patients from the lingering complications of post-ICU syndrome long after they leave the hospital. 

Learn more about CIRCLE on its program page.