When the long and difficult search for the HLA-linked gene was finally brought to a conclusion by the cloning of HFE, it was generally thought that the discovery of this elusive molecule would provide us with true insight into how body iron is regulated. After all, mutation of this gene was known to cause iron overload—sometimes very severe iron overload. But the discovery of the HFE gene raised more questions than it answered and served as a powerful stimulus for the application of the methods of modern molecular biology to the problem of iron homeostasis. Thus, as a result of the use of database search, positional cloning, knockout mice, injection of pooled RNA, and subtraction cloning, new actors in the arena of iron homeostasis were discovered: transferrin receptor 2, DMT1, ferroportin, hephaestin, duodenal cytochrome b, and, probably most interesting of all, hepcidin.
In this issue (page 783) Tomas Ganz, the discoverer of hepcidin as a antimicrobial peptide, provides the reader with an incisive review of the complex structure and of the probable physiologic action and regulation of this small polypeptide. Not only does hepcidin appear a key regulator of body iron content, but it may play an important role in defense against infection by depriving microorganisms of a ready source of iron. Thus, hepcidin may prove to be an important key to understanding of one of the most common anemias of all, the anemia of chronic disease. This is a fertile area for further research, and in the Ganz article there are ample provocative suggestions for additional studies.