Red blood cells have learned to borrow what they cannot make
For decades, a quiet mystery persisted at the heart of human biology: how do red blood cells continue building hemoglobin after discarding the very machinery required to make it? A team at the University of Maryland has now answered that question, discovering that stressed red blood cells borrow heme from neighboring cells through a protein called HRG1 — a molecular act of communal survival. The finding reframes hemoglobin production not as a solitary cellular achievement but as a cooperative one, and in doing so, opens a new frontier for treating sickle cell disease and beta-thalassemia, conditions where that cooperation has broken down.
- Millions of patients with sickle cell disease and beta-thalassemia endure chronic pain and organ damage because their red blood cells cannot maintain healthy hemoglobin — a problem science has lacked the tools to fully address.
- The discovery that red blood cells import heme from neighboring cells via the HRG1 protein upends longstanding assumptions about how hemoglobin synthesis works after mitochondria are shed.
- Mice engineered without HRG1 collapsed under low-oxygen stress, their developing blood cells dying before maturity — confirming the pathway is not optional but essential under pressure.
- In a counterintuitive twist, partially blocking HRG1 in beta-thalassemia mice reduced toxic heme buildup and actually improved red blood cell production, revealing the pathway cuts both ways therapeutically.
- Researchers are now hunting for molecules that can fine-tune HRG1 activity, aiming to translate this biological discovery into drugs that restore balance in blood disorders driven by heme imbalance.
Red blood cells accomplish something paradoxical: they load themselves with hemoglobin — the protein that carries oxygen through the body — after discarding the nucleus and mitochondria needed to produce it. For decades, this contradiction went unexplained. Now, a team led by Iqbal Hamza at the University of Maryland School of Medicine has found the answer, published in Science: a protein called HRG1 allows stressed red blood cells to import heme directly from neighboring cells, bypassing their own lost machinery entirely.
Hamza's team demonstrated the mechanism by engineering mice unable to produce HRG1. Under low-oxygen conditions, these animals could not ramp up red blood cell production — developing cells starved of heme and died before reaching maturity. The conclusion was unambiguous: HRG1 is not a redundancy but a necessity when the body demands rapid blood cell renewal.
The therapeutic implications proved more surprising. Beta-thalassemia causes heme to accumulate to toxic levels inside cells, driving inflammation and oxidative damage. When researchers partially suppressed HRG1 in a beta-thalassemia mouse model, red blood cell production improved — because reducing heme import lowered the toxic burden while the body compensated with healthier cells. The logic is counterintuitive, but the results were clear.
Sickle cell disease, where mutated hemoglobin distorts red blood cells into their damaging sickle shape, may be similarly addressable. Mark Gladwin, dean of the University of Maryland School of Medicine, described the discovery as opening "exciting therapeutic possibilities" across a wide spectrum of blood disorders driven by heme imbalance. The next step is identifying molecules that can modulate HRG1 levels — finding the switches to a pathway that, until now, no one knew existed.
Red blood cells face an impossible task: they must pack themselves with hemoglobin, the protein that ferries oxygen through the body, yet they accomplish this feat after discarding the very machinery needed to make it. They jettison their nucleus and mitochondria—the cellular structures that contain DNA and produce heme, the iron-containing molecule essential for hemoglobin synthesis. For decades, scientists puzzled over how these cells continued manufacturing hemoglobin after losing the means to do so. A team led by Iqbal Hamza at the University of Maryland School of Medicine has now found the answer, and it points toward new treatments for sickle cell disease and other blood disorders.
The discovery centers on a protein called Heme Responsive Gene 1, or HRG1, which acts as a molecular importer. When red blood cells are under stress—when the body needs them to multiply rapidly due to low oxygen, blood loss, or other demands—they use HRG1 to pull heme from neighboring cells, bypassing the need for their own defunct mitochondria. The finding, published in Science, reveals what researchers call a "cell-nonautonomous heme acquisition pathway," meaning red blood cells have learned to borrow what they cannot make themselves.
Hamza's team demonstrated this mechanism by engineering mice incapable of producing HRG1. When these animals were exposed to low-oxygen conditions, their bodies struggled to ramp up red blood cell production as they normally would. The developing blood cells lacked sufficient heme and died before reaching maturity, unable to synthesize enough hemoglobin to survive. "We've shown that this transporter protein, HRG1, is essential for the production of healthy, mature red blood cells, particularly at a time when the body needs to produce red blood cells quickly," Hamza explained. The implication was clear: without HRG1, the system breaks down under pressure.
But the pathway's therapeutic potential emerged from an unexpected direction. Beta-thalassemia, a blood disorder characterized by defective hemoglobin production, causes the opposite problem: heme accumulates to toxic levels inside cells, triggering inflammation and oxidative damage. When researchers partially suppressed HRG1 in a mouse model of beta-thalassemia, red blood cell production actually improved. The logic is counterintuitive but sound—by reducing the cell's ability to import heme, they lowered the toxic buildup while the body compensated by producing healthier cells.
Sickle cell disease, caused by a mutated hemoglobin that polymerizes and distorts red blood cells into their characteristic sickle shape, may benefit from similar approaches. Mark Gladwin, dean of the University of Maryland School of Medicine, noted that the findings "extend to a wide spectrum of blood disorders—including sickle cell disease and beta-thalassemia—where heme imbalance drives inflammation, oxidative stress, and organ damage." The discovery of HRG1 as a regulator of heme availability, he said, "opens exciting therapeutic possibilities for conditions in which the body struggles to maintain healthy red cell production."
The next phase of research will focus on identifying molecules that can modulate HRG1 levels—essentially finding the switches that control this newly discovered pathway. If scientists can develop drugs that fine-tune HRG1 activity, they might be able to restore balance in blood disorders where hemoglobin production has gone awry. For patients with sickle cell disease, who endure chronic pain, organ damage, and shortened lifespans due to their misshapen red blood cells, such a therapeutic approach could represent a fundamental shift in treatment. The pathway Hamza's team uncovered suggests that sometimes the most promising cures come not from forcing cells to work harder, but from understanding how they adapt when the pressure is on.
Notable Quotes
HRG1 is essential for the production of healthy, mature red blood cells, particularly when the body needs to produce them quickly due to stresses like oxygen deprivation or blood loss.— Iqbal Hamza, senior author and professor at University of Maryland School of Medicine
Identifying HRG1 as a regulator of heme availability opens exciting therapeutic possibilities for conditions in which the body struggles to maintain healthy red cell production.— Mark Gladwin, dean of University of Maryland School of Medicine
The Hearth Conversation Another angle on the story
Why does it matter that red blood cells can import heme from other cells? Couldn't they just make their own?
They would if they could. But mature red blood cells deliberately destroy the machinery that makes heme—their mitochondria—to make room for more hemoglobin. It's a trade-off. They gain oxygen-carrying capacity but lose the ability to manufacture heme. HRG1 lets them cheat that trade-off by borrowing from neighbors.
And in sickle cell disease, why would controlling HRG1 help? The problem is the hemoglobin itself is malformed.
True, but the malformed hemoglobin creates a cascade of problems—inflammation, oxidative damage, organ failure. Some of that damage comes from heme imbalance. By controlling HRG1, you're not fixing the mutation, but you're reducing the collateral damage the mutation causes.
So you're treating the symptom, not the disease.
In a sense, yes. But for patients suffering now, reducing organ damage and inflammation could be transformative, even if it doesn't cure the underlying genetic defect.
The beta-thalassemia results seem backwards—blocking HRG1 made things better?
Because beta-thalassemia has the opposite problem. Heme builds up to toxic levels. By reducing the cell's ability to import more heme, you lower the poison while the body adapts by making healthier cells overall.
What's the next hurdle?
Finding drugs that can safely modulate HRG1 without disrupting normal red blood cell production. It's a narrow target. Too much suppression and you harm healthy cells. Too little and you don't help the sick ones.