Essential but toxic
by Julie Kinney
Joanne Levy joined the lab of Nancy Andrews because she wanted to find answers. And Andrews' team was on its way to answering baffling questions related to how iron is transported throughout the body.
Levy, then a fellow in adult oncology and hematology, was tired of seeing patients die from iron diseases. But it was the death of a young man from a unique combination of iron overload and iron deficiency that closed the deal for her. The traditional therapies simply didn't work. Removing blood and transfusing blood were both deadly in his case. "These conditions shouldn't have been so harmful," says Levy. "I thought, 'I have to do something about this.' "
While a necessity, iron is also toxic in excess. In a balanced state, only 1 to 2 milligrams of iron enter and exit the body each day via the digestive tract. That is the same amount of iron as is found in about half a teaspoon of normal blood. About 3,000 times that much iron is needed for the normal functions of the body. To maintain iron balance and avoid problems that result from too much or too little, the body has devised intricate systems for conserving and recycling its iron.
Iron is essential for hemoglobin to perform its job of carrying oxygen through the bloodstream and of producing energy. However, iron doesn't move in and out of cells easily, and until recently, little was understood about how iron enters the body and finds its way to where it is needed. In essence, iron must hitch a ride with a particular gene to penetrate a cell. Andrews and her colleagues found this driving gene in 1996. This finding, along with continued research into the cellular machinery needed to transport iron, is expected to lead to better understanding of and eventually better therapies for the millions suffering from iron overload or iron deficiency.
Some one billion people worldwide are affected by disorders of iron balance. Iron deficiency, most commonly associated with anemia, affects 600 million people or more throughout the world’Äîenough to populate just over two countries the size of the United States. Iron deficiency leaves its victims fatigued and can disturb neurological functioning. In its most extreme manifestation, it results in a bizarre behavioral disorder known as pica, in which patients compulsively eat non-nutritive substances such as ice, salt and clay. And, in children, iron deficiency can cause measurable cognitive disruptions.
"Iron is especially critical to infants and women of child-bearing age. Children need more early in life to support their rapid growth, and women need it to replace iron lost through menstruation," says Andrews, an attending physician in Hematology and Oncology at Children's and Dana-Farber Cancer Institute and an investigator with the Howard Hughes Medical Institute. "Today, 5 percent of toddlers and up to 10 percent of adolescent girls in the United States have iron deficiency."
At the other end of the spectrum, iron overload diseases, such as hemachromatosis, are very common in both European and African populations and can lead to liver failure, arthritis, diabetes, impotence and heart problems if left undetected.
Ironically, iron balance problems can also be caused by lifesaving treatments. Repeated transfusions can lead to rapid iron loading, depositing too much iron in certain organs. Children's physicians hope that new understanding may lead to therapies that alleviate the iron burden acquired by patients on long-term transfusion therapy for intractable anemia, which can result from thalassemia, bone marrow failure or aggressive treatment of cancer.
Andrews' lab has been studying 15 different strains of mice with genetic defects disrupting their iron balance. Some of these mice have inborn errors of iron metabolism; others have been engineered to harbor exact copies of human iron diseases. For example, the lab has produced mice with the same genetic defect as human patients with the most common type of hemachromatosis, which involves a single error in the genetic blueprint for a protein called HFE. "We think about the mice much as we think about our human patients with iron problems," says Andrews, "but the fact that they are lab animals allows us to probe more deeply into their problems than we would with people."
Physicians follow patient for iron overload
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The mouse "iron clinic" has allowed Andrews and her colleagues to discover components of the machinery carrying iron into and out of a cell. They have identified specific mutations that lead to opening of cellular barriers and allow far too much iron in, as well as those that contribute to a total iron lockout. Either way, the iron balance within the body is disabled, which can lead to the poisoning of organs if too much iron accumulates, or anemia when not enough is present.
These spontaneous and engineered mutations are helping to define the function of proteins involved in iron metabolism and identify targets for drug design. For example, Andrews' group has found that iron loading in mice with hemachromatosis occurs only when iron can hitch a ride into the body with the protein DMT1. This insight may lead to the development of drugs that specifically target and block DMT1 function in the intestinal cells that absorb dietary iron.
Assisted by these genetic insights, clinicians will be better equipped to test for iron accumulation and to intervene in cases of iron deficiency, which can remain disguised due to the often common symptoms that accompany it: pallor, fatigue, poor exercise tolerance and decreased work performance.
"Already, diagnostic testing for mutations in the gene that produces HFE has markedly changed our clinical approach to hemachromatosis," says Andrews. "We now have a definitive test for the most common type of hemachromatosis. This test has made us aware that there are non-HFE forms of the disease, and now we can distinguish one from the other. It is likely that molecular diagnostics will soon be available for other iron-loading disorders and for inherited defects in iron absorption and use."
Despite these tremendous strides leading to therapies for people suffering from iron deficiency and iron overload disorders, plenty of challenges remain. "There doesn't appear to be a silver bullet," she says. "Researchers are only now beginning to understand how complex iron overload can be. And relatively little is understood about the risks for children who are predisposed to iron overload. These will be important areas for future investigation."
