A new discovery about how the body makes red blood cells could lead to improved treatments for anemia.

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A new discovery about red blood cells may lead to new treatments for anemia.

Researchers at the University of Virginia School of Medicine in Charlottesville made the discovery while investigating why the body fails to make enough red blood cells in iron-restricted anemias.

They report their findings — which concern the role of the hormone erythropoietin (EPO) in the production of red blood cells — in the Journal of Experimental Medicine.

Anemia is a blood disorder in which either the body has insufficient red blood cells for carrying oxygen to tissues, or the red blood cells are faulty and cannot do their job properly. This can lead to weakness, fatigue, poor concentration, and other symptoms.

Worldwide, anemia is a huge health problem that affects more than 1.6 billion people.

In the United States, anemia is a “growing problem.” Its prevalence nearly doubled from 4 percent to 7 percent in the period 2003–2004 to 2011–2012.

There are many types and causes of anemia. The most common relate to lack of iron, which the body needs to make hemoglobin, the protein in red blood cells that helps them to carry oxygen.

Iron is also vital to other biological functions, and the body has evolved several ways of conserving the element, including recycling it from broken down red blood cells.

Too much iron can be toxic, and the body has mechanisms that ensure that it stays within safe levels. For example, it limits absorption and meets most of its daily need from recycling.

Red blood cells are made in bone marrow in an intricate process that is controlled by the hormone EPO.

EPO sends instructions to bone marrow stem cells, which receive them through EPO receptors on their outside surfaces.

However, lead author Shadi Khalil, a doctoral student in Prof. Goldfarb’s group, noticed something surprising while examining bone marrow cells in the laboratory: he noticed that they contained lots of EPO receptor inside them, but not on their outside surfaces.

This made him wonder if the reason that EPO hormone instructions fail in some people is because their bone marrow cells do not have enough EPO receptors on their surfaces.

After running some tests on mice, the researchers found the answer to the question – at least partially. They found that “mice with enforced surface retention of the receptor fail to develop anemia with iron deprivation.”

However, there was still another piece of the puzzle to find.

It turned out that another member of the team was already working on the missing piece. This work showed that if iron levels drop too low, a particular protein that regulates the EPO receptor vanishes. The protein — which is coded by the SCRIB gene — is called Scribble.

“Scribble deficiency reduces surface expression of Epo receptor but selectively retains survival signaling,” note the authors.

In other words, they discovered that iron levels in the blood affect the level of Scribble, which, in turn, decides whether EPO receptors gather inside or on the outside of the bone marrow cells.

“We realized,” explains Khalil, “that this was kind of a complicated symphony that starts with iron and ultimately controls how much and what kind of messages the cells get.”

The researchers hope that their discoveries about how to “fix EPO resistance” will lead to new treatments for anemia.

“We’ve got the key components,” says Prof. Goldfarb, summing up the findings and pointing to the next step, “and we want to move up the hierarchy to the master regulatory element that’s controlling this.”

When we do that, that will get us that much closer to alternative treatments for anemia.”

Prof. Adam N. Goldfarb