Charmaine Royal Leads $5 Million Effort to Decode Sickle Cell Pain

What if one disease could unlock insights into dozens of diseases? This is the ambition underlying a new federal grant led by Charmaine Royal, Professor of African & African American Studies and Biology, which aims to transform how researchers and clinicians understand pain in people living with sickle cell disease, moving beyond one-size-fits-all approaches to capture the complex realities of individual patient experiences. 

Sickle cell disease refers to a group of inherited blood disorders characterized by the predominance of sickle hemoglobin (HbS), caused by an alteration in a single gene: the hemoglobin subunit beta, or HBB, which is responsible for the production of hemoglobin — the molecule that binds to oxygen inside red blood cells.  

Many people carry one copy of the altered gene — the sickle cell trait — and typically present no signs or symptoms of sickle cell disease. In the United States, the prevalence of sickle cell trait is higher in people with recent African ancestry, but it can be found in people of any ethnic background, particularly from parts of the world where malaria was or is present. 

To inherit the most common form of sickle cell disease, sickle cell anemia (HbSS), a person must receive one copy of HbS from each parent. Instead of the typical round and flexible red blood cells, HbS leads to the production of crescent-shaped, short-lived and rigid red blood cells.  

These are not only far less efficient at delivering oxygen to the body but are also more likely to cause blockages due to their shape and rigidity. The result is a wide range of symptoms in people with sickle cell disease, from anemia to a heightened risk of strokes, severe and unpredictable pain episodes, and chronic organ damage. How symptoms appear and how severe they become varies greatly from patient to patient.

"This is the kind of work that could help take us away from genetic determinism and towards a deeper understanding of how environment, genes and health interact."

To Royal, the relatively simple genetic inheritance underlying sickle cell disease, paired with its unique scientific history and the complex range of symptoms it causes, makes it a perfect model to understand disease evolution and progression. Her team’s project, funded through the National Institutes of Health’s NIH HEAL Initiative, brings together researchers, clinicians and patients in what the team describes as a “whole person health” approach to sickle cell pain.  

“This is beyond interdisciplinary research,” said Royal. “It’s convergence research, integrating knowledge from diverse academic disciplines with that from other sectors to solve complex problems and produce new theories, frameworks and/or paradigms.” 

Pain is the leading cause of hospitalization among people with sickle cell disease and is associated with increased health complications, mortality and healthcare costs. Yet despite decades of research, many aspects of sickle cell pain remain poorly understood.  

The new study seeks to address that gap by examining not only biological and clinical factors but also the behavioral, psychological, environmental, sociocultural and structural influences that shape pain experiences over time.  

The project will unfold over five years with a budget of $5 million. It is organized around three major aims. 

First, in collaboration with the Globin Research Network for Data and Discovery (GRNDaD), a large multi-site sickle cell registry, the research team will develop “Baseline Pain Profiles” using existing registry data from approximately 4,500 patients to identify broad patterns in how individuals experience pain.  

Second, researchers will recruit 1,250 new patients with sickle cell disease from about six different GRNDaD sites to create more detailed “Precision Pain Profiles.” For each of these new patients, the team will collect expanded information about pain severity, pain types, duration and frequency of acute episodes, as well as whole genome sequences and data from the behavioral and other domains, through a three-year prospective cohort study. The goal is to better distinguish different pain experiences and identify potential targets for prevention and treatment. 

Third, the team will develop computational and statistical models that integrate diverse forms of data to better understand why precision pain profiles differ across individuals and why treatments vary in effectiveness from one patient to another. The project will use machine learning and other advanced analytical approaches to model relationships among biological, clinical, social and other factors. 

“This is beyond interdisciplinary research. It’s convergence research, integrating knowledge from diverse academic disciplines with that from other sectors to solve complex problems and produce new theories, frameworks and/or paradigms.” 

Royal said the project is rooted in partnership. The collaboration includes Duke faculty and staff across multiple schools and fields, consultants from other universities, industry and government partners, clinicians and researchers affiliated with the National Alliance of Sickle Cell Centers and patient support and advocacy groups. 

The team is also establishing a Citizen Scientist Advisory Board comprised of people living with sickle cell disease and expanding engagement with students, trainees and community partners throughout the project. “The involvement of these stakeholders is as important as the science itself,” said Royal. 

Researchers hope the work will ultimately lead to more personalized and effective strategies for pain prevention, intervention and treatment for people living with sickle cell disease. 

Royal said that it took multiple iterations over many years for the project to receive unanimous enthusiasm from NIH reviewers and be funded. In 2002, while planning a different grant, she surmised that sickle cell disease could serve as a model for understanding other diseases with more complex etiologies. One of her mentors commented, “This is the kind of work that could help take us away from genetic determinism and towards a deeper understanding of how environment, genes and health interact. I hope one day you get to do it.”

“The idea never left me,” Royal said. “I have dreamt about this project for more than 20 years.”