Molecular methods to analyze sickle cells provide deeper insight into therapeutics

Caused by the abnormal polymerization of hemoglobin molecules, sickle cell disease creates deformations in red blood cells (RBCs) that lead to sometimes fatal perturbations in cellular behavior and rheological characteristics in blood. New small molecule drugs and gene therapy are poised to ameliorate these effects but have also cast light on knowledge gaps for how these ordered fiber structures behave.

Williams et al. explored how these emerging therapies are expected to shift the rheological and cellular alterations associated with sickle cell disease away from vaso-occlusive crises and other dangerous sequelae. They surveyed microchip assays for analyzing how therapies affect a range of parameters central to assessing therapeutic efficacies, including RBC shape and the vascular microenvironment.

“I’m excited about the idea that we can theoretically, experimentally, and computationally link what’s happening at the scale of molecules to what’s happening at the scale of a whole human,” said author David Wood. “The way forward is to show mechanistically and quantitatively how the processes at each scale are linked to the next - molecules to cells to whole blood to a human.”

Higher throughput microfluidic devices assess the viscoelastic properties of affected RBCs, including methods for applying consistent hydrodynamic shear to RBCs under controlled oxygen tension.

Bulk viscometry provides links between the deforming of RBCs and resulting vasculopathies, including stroke and hemolytic anemia. Spatially resolved flow measurements have provided ways to model more complex circumstances, such as bifurcating networks and geometric confinement.

Such methods could improve small molecule therapies while gene therapies become more affordable, Wood said.

The researchers plan to continue developing methods for evaluating sickle cell therapies and predict their clinical outcomes.

Source: “Sticking together: Polymerization of sickle hemoglobin drives the multiscale pathophysiology of sickle cell disease,” by Dillon C. Williams, Hannah M. Szafraniec and David K. Wood, Biophysics Reviews (2025). The article can be accessed at https://doi.org/10.1063/5.0238698 .

This paper is part of the Biomolecular Phase Transitions and the Mechanochemical Control of Cells in Health & Disease Collection, learn more here .