Tracking a Hidden Engine: UCSF Develops New Biomarker for Sickle Cell Disease
For years, the story of sickle cell disease revolved the iconic "sickle" shape of affected red blood cells and the outbreaks of debilitating pain that patients experience. Now, UCSF researchers have developed a new way to look inside red blood cells — uncovering hidden mitochondria that may be driving disease severity and offering doctors a powerful new tool to measure whether breakthrough treatments are working.
In a new study published in eJHaem, scientists from UCSF’s Division of Pediatric Hematology reveal a novel way to measure this concealed feature of the disease. By combining two advanced lab techniques, the team has created a method that not only shows how many red blood cells still hold onto mitochondria, but also how many of these tiny engines each cell contains.
This dual-assessment tool could provide researchers and clinicians with a new benchmark for evaluating today’s most advanced sickle cell therapies, including CRISPR gene editing and recently approved gene replacement treatments.
The Problem with Leftover Mitochondria
As red blood cells mature, they need to get rid of all their internal machinery, including mitochondria, the tiny power plants of the cell that consume oxygen and produce energy. This cleanup process, called mitophagy, creates streamlined cells perfect for carrying oxygen.
Angela Rivers, MD, PhD, professor of pediatrics at UCSF and senior author on the paper, originally discovered in her lab that this cleanup often fails in SCD, leaving behind mitochondria in some mature red blood cells.
“Think of it like having old, inefficient engines still running in your car,” explains Rivers. “These red blood cells consume fuel (oxygen) that should go to tissues, produce harmful exhaust (reactive oxygen species), and make the whole system less stable. These retained mitochondria are believed to worsen the effects of sickle cell severity in at least four different ways.”
UCSF's Innovation: A More Complete Test
Previously, scientists could only determine how many of a patient's red blood cells retained mitochondria, using a technique called flow cytometry.
The UCSF team combined this with a precise DNA quantification technique to create a new dual-assessment method that also finds how many mitochondria are packed inside each cell.
“Whereas the previous technology identified the presence of some mitochondria in about 11% of the red cells in our study cohort, we now have established that each of those 11% of cells contains an average of 400 mitochondria,” says Rivers. “These high numbers further emphasize the critical need to further assess the impact of mitochondria on the disease.”
A New Benchmark for Sickle Cell Therapies
This breakthrough provides a new, more precise biomarker that is crucial for developing and testing new treatments, including the CRISPR trial led by Mark Walters, MD.
“For gene therapy and other cutting-edge treatments, we need reliable biomarkers that can tell us whether the treatment is working at the cellular level before we see changes in clinical symptoms,” Rivers notes. “Therapies can now be assessed for their efficacy in reducing both the size of the red blood cell fraction retaining mitochondria and the mitochondrial load in each cell.”
The research team hopes that this new tool will help clinicians and researchers in several ways, including:
- Monitoring disease severity more precisely.
- Evaluating whether new treatments are working at the cellular level.
- Predicting which patients might benefit most from specific therapies.
From the Lab to the Patient
Moving forward, the team plans to use their new method to conduct more robust analyses of how mitochondrial retention relates to the organ damage that harms many patients with SCD. By better understanding these cellular disturbances, they aim to uncover new therapeutic approaches to promote the cell's cleanup process, mitigate harmful inflammation, and ultimately improve patient outcomes.
“What's particularly exciting about this work is that it bridges basic science discoveries with practical clinical applications,” says Rivers. “We're not just measuring something interesting in the lab—we're developing tools that could directly impact patient care and treatment development. This kind of precise biomarker could be especially valuable as we move toward personalized medicine approaches for SCD.”
By giving scientists a clearer window into what’s happening inside each red blood cell, this work brings us closer to making cures for sickle cell disease not just possible, but lasting.
Authors: Other UCSF authors include Eric Soupene, PhD, Hart Horneman, Mikail Alejandro, Kenzy Mohammed, and Yaw Ofosu Nyansa Ansong‐Ansongton.
Funding: This work was supported by grants from the National Lung, Blood, and Heart Institute (5R01HL136622‐04) and the National Institute of Neurological Disorders and Stroke (1R21AT012304‐01).