During the last decade there has been a surge of interest and activity in exploring the metabolic links between
copper and
iron. This review describes more than a century and a half of effort that has led to our current understanding. Particular attention is given to the early events since these are less well-known and appreciated. The landmark 1928 paper of Hart, Elvehjem and coworkers is generally given credit for the start of the
copper/
iron field, and specifically for the discovery of the role of
copper in forming
hemoglobin and in overcoming
anemia. However, some credit for the ideas, observations, and experiments should be shared with several investigators of the previous century. These scientists and physicians were primarily motivated to find the causes and cures of
chlorosis, a common form of
anemia at the time. From his chemical determination of
copper in red blood cells in 1848, Millon proposed a form of
chlorosis due to
copper deficiency. Likewise, Pécholier and Saint-Pierre, observing the robust health of young women working in
copper factories, concluded that
copper was helpful in preventing and overcoming
chlorosis. The first direct experimental evidence for the theory was provided by the Italian physician Mendini, who in 1862 reported that supplementation of the diet with
copper salts overcame
chlorosis in young women. In the 1890s Cervello and his students in Italy, using semi-quantitative hematological measurements, confirmed the beneficial effects of
copper on
anemia both in patients and in animal models. There was nearly a 30-year period of inactivity, but the decade of the 1930s saw renewed interest and exciting developments in the field. The Elvehjem report of 1928 was quickly verified and extended by multiple laboratories on four continents. In the 1950s and 1960s Wintrobe and Cartwright and their colleagues localized, and started to systematically evaluate, the potential sites at which
copper was likely to effect
iron for
hemoglobin synthesis, namely, intestinal absorption, release from storage, and cellular utilization during synthesis. The
copper/
iron connection also has a 'flip-side', i.e.,
iron status can influence
copper metabolism as first described by Warburg and Krebs in 1927. Thus, there are opportunities for feedback mechanisms at the cellular and physiological level that are not yet understood. The evaluation of these processes continues to this day, aided by modern molecular and genetic approaches. Studies of two
copper proteins,
ceruloplasmin and its recently discovered homologue hephaestin, have provided two molecular links connecting the pathways of
copper and
iron metabolism. The recent identification of other
proteins of
iron and
copper metabolism, for example,
copper ATPases and the membrane
iron transporters DCT1/DMT1/Nramp2 and IREG1/MTP1/ferroportinl, are likely to fill crucial pathway gaps. The ongoing discovery of genes and gene mutations involved in the metabolism of
copper and
iron provides an important key to a deeper understanding of the connections between the pathways, and their physiological and pathological consequences. It is hoped that this historical review, by illuminating the complex paths that have led to the current state of knowledge, will contribute to our appreciation, our understanding, and perhaps our continued discovery of the connections between
copper and
iron.