In Focus
Cracking the code of blood
How genetics and metabolism are transforming transfusions
Every two seconds, someone in the United States receives a red blood cell transfusion. For more than a century, matching blood type has been the cornerstone of transfusion safety. Yet even when compatibility is perfect, some transfusions seem to “take” better than others.
Patients receiving blood from one donor recover quickly, while others gain less hemoglobin or experience faster red cell breakdown. What makes the difference? New studies suggest the answer lies in our genes and the chemistry of our blood — an intersection of genetics, metabolism, and evolution that is changing how we think about transfusion medicine. In the last few years, research teams across the world have been decoding how subtle differences in our DNA influence the resilience of stored red cells. In one large multi-ancestry study published in the Journal of Clinical Investigation, my colleagues and I scanned the genomes of thousands of blood donors to identify genetic variants linked to red cell fragility during storage. We found 27 genomic “hotspots,” many within genes that shape the red cell membrane or skeleton, such as SLC4A1 and SPTA1. Others traced back to variants selected during humanity’s long battle with malaria, showing how evolutionary pressures still echo in modern blood storage and transfusion outcomes. The lesson was clear: blood is not as universal as we once thought. Its quality, even before it leaves the donor, reflects individual biology.
Follow-up studies have shown that these genetic fingerprints can have real clinical impact. Work by Roubinian and colleagues demonstrated that both genetic and environmental factors in the donor affect how much hemoglobin a patient gains after transfusion. This “donor effect” confirms what clinicians have long suspected — that two units of blood from different people may not be functionally equivalent. As a population geneticist, I find this deeply exciting: we’re beginning to see how population diversity, once viewed mainly as a challenge for blood supply, can actually inform a more precise and effective use of donated blood.
Parallel breakthroughs are coming from metabolomics, which measures the thousands of small molecules circulating in red cells. This approach captures how red cells respond to storage, stress, and disease. Researchers at the University of Colorado and others have linked specific genetic variants to the metabolism of amino acids, lipids, and antioxidants in stored blood. One Blood study found that differences in tryptophan metabolism — specifically the pathway leading to kynurenine — predict how well red cells withstand oxidative stress. Another revealed that carnitine, a molecule best known for its role in energy metabolism, helps repair lipid damage and stabilize cell membranes. Donors whose genetic profiles favor efficient carnitine metabolism produce red cells that last longer in storage and in the circulation after transfusion.
A separate line of work, also in Blood, has brought attention to ferroptosis — a form of iron-driven, lipid-mediated cell death. This process, better known in cancer biology, turns out to be a key driver of red cell breakdown during storage. Blocking ferroptosis in experimental models helps preserve red cell integrity, hinting that future storage solutions could target this pathway to extend shelf life and improve transfusion efficacy.
The implications extend beyond storage. In Aging Cell, researchers showed that certain metabolic signatures in red cells, particularly in arginine and nitric-oxide pathways, mirror the biological age of the donor. These findings suggest that blood may carry its own “molecular clock,” revealing the physiological state of the person who gave it — a tantalizing prospect for population health monitoring.
Figure 1. From genes to metabolite science is increasing our understanding of Red Blood Cells and unlocking safer and more effective transfusions.
Together, these discoveries are ushering in an era of precision transfusion medicine. Large research programs like REDS-IV-P are already integrating genomic, metabolomic, and clinical data from tens of thousands of donors and recipients to understand what makes an optimal transfusion match. The vision is to identify “super donors” whose blood stores better and benefits patients most, while tailoring transfusions to individual needs — not just by blood type, but by biology.
For transfusion practitioners, these advances will eventually move from the lab to the blood bank. In the future, genetic and metabolic screening could inform how blood products are stored, selected, or prioritized for vulnerable patients such as newborns or those requiring chronic transfusions. More immediately, this growing body of evidence invites us to think differently about what a unit of blood represents. Each bag is not just a collection of cells but a reflection of a person’s genetic heritage, diet, age, and life history — a microcosm of human diversity.
Blood transfusion, one of medicine’s oldest therapies, is thus becoming one of its most modern frontiers. By reading the genetic and metabolic code written into every red cell, we are beginning to transform a century-old practice into a precision science — one that honors both the individuality of donors and the needs of the patients they help.
References
- Page GP et al. Multiple-ancestry genome-wide association study identifies 27 loci associated with measures of hemolysis following blood storage J Clin Invest. 2021;131:e146077.
- Roubinian NH et al. Donor genetic and nongenetic factors affecting red blood cell transfusion effectiveness JCI Insight. 2022;7:e152598.
- Nemkov T et al. Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo Blood. 2024;143:456–472.
- D’Alessandro A et al. Ferroptosis regulates hemolysis in stored murine and human red blood cells Blood. 2025;145:765–783.
