Forging A Field: The Golden Age of Iron Biology: ASH 50th Anniversary Review

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ASH 50th anniversary review
Forging a field: the golden age of iron biology

Nancy C. Andrews1
1Duke University School of Medicine, Durham, NC
Introduction
Oh what a difference a decade makes! In a landmark paper In contrast, transferrin is actively secreted by hepatocytes, the
published in 1996, Feder and colleagues identified the long-sought cells that express it most vigorously. Transferrin is also produced
gene mutated in patients with classical hereditary hemochromato- on the sanctuary sides of the blood/testes barrier, by Sertoli cells,
sis. In many ways, this seemed to ignite an explosion in iron and the blood/brain barrier, by several distinct cell types. It serves
biology which, over the next 10 years, led to a remarkably detailed the general purpose of binding iron, keeping it soluble in an
(though still incomplete) understanding of the pathophysiology of aqueous environment and delivering it to tissues. The mammalian
hemochromatosis. Many discoveries critical for understanding iron transferrin molecule has 2 similar iron-binding lobes, each capable of
homeostasis, however, were kindled by earlier work dating back holding one atom. Lower eukaryotes have transferrins analogous to 1 of
half a century and more. This review will emphasize advances the 2 mammalian lobes. It has been proposed that the double site
made between the birth of the American Society of Hematology transferrin molecule evolved at the same time that functional kidneys
(ASH) in 1958 and the present. In the early part of that period, appeared, increasing the size of the protein to prevent loss by filtration.9
ferrokinetic studies provided important insights into human iron Transferrin keeps iron nonreactive in the circulation and in
homeostasis in vivo (reviewed in Finch et al1). More recently, extravascular fluid, delivering it to cells bearing specific transferrin
modern molecular biology and genetic studies of model organisms receptors. The classical transferrin receptor, TFR1, is found in
have extended our knowledge of normal iron biology and led to largest amounts on rapidly dividing cells, on activated lympho-
detailed understanding of human iron disorders. Ironically, a cytes, and on erythroid precursors. It selectively binds diferric
comprehensive review on iron metabolism appeared in Blood transferrin to internalize it through a constitutive pathway of
exactly 50 years ago, describing a current state of knowledge that receptor-mediated endocytosis (the transferrin cycle), which has
was viewed as quite complete at the time.2 Adding to the irony, that become a paradigm in cell biology (Figure 1).
author, Hugh Josephs (another pediatric hematologist), had To initiate the transferrin cycle, patches of cell-surface mem-
54 journal pages and I only have 12! brane carrying receptor-ligand complexes invaginate to form
clathrin-coated endosomes. After clathrin is removed the endo-
Cellular regulation of iron homeostasis somes become acidified through proton influx, leading to conforma-
tional changes in both transferrin and TFR1, and promoting iron
The earliest molecular studies of iron metabolism focused on
release. Liberated inorganic iron is then reduced by the ferrireduc-
2 molecules that are both abundant and easy to isolate. In
1937, horse spleen ferritin was the second of all proteins to be tase STEAP3 to Fe2⫹,10 which is the substrate for transmembrane
crystallized.3 Transferrin was identified as an abundant plasma iron transport by divalent metal transporter 1 (DMT1 or SLC11A2,
transport protein a decade later.4 Both of these molecules are now formerly called NRAMP2, DCT1).11-13 Both STEAP3 and DMT1
used clinically in assays of iron status. Both ferritin and transferrin were discovered through positional cloning of genes altered in
sequester iron to keep it nonreactive, thus precluding the Fenton rodents carrying spontaneous mutations impairing iron trans-
chemistry that promotes formation of oxygen radicals. But they do port.10,11 The use of mutant animal models to identify key iron
so in very different ways. Ferritin, which has homologs in all transport molecules has been remarkably productive, and a hallmark of
organisms except yeast, is a cagelike heteropolymer of 24 subunits work of the past decade (reviewed inAndrews14). This powerful strategy
of H- (heavy or heart) and L- (light or liver) types, which can hold takes advantage of mutants discovered and maintained over the last
up to 4500 iron atoms.5 As pointed out by Munro, it is unique century, analyzed using modern genetic techniques.
among enzymes in that it stores its substrate after acting upon it.6 Gunshin13 and Hediger15 showed that DMT1 is electrogenic,
H-ferritin is slightly larger than L-ferritin, and has ferroxidase requiring proton cotransport to move Fe2⫹ across the membrane.
activity important for movement of iron into the solid-state core of This need is met by the low pH milieu of the transferrin cycle
the protein. Most ferritin is used to store within cells, but a very endosome (internal pH approximately 5.5). The subsequent fate of
small amount enters a distinct secretory pathway, destined for iron that exits the transferrin cycle endosome is not well under-
glycosylation and release into the serum. Aside from its useful role stood, but in erythroid cells most is needed for heme biosynthesis.
as a semiquantitative indicator of iron stores, the biologic purpose To make heme, iron must again cross an ion-impermeable mem-
of serum ferritin remains unknown. Ferritin receptors are present brane to enter the mitochondrion. The mitochondrial iron importer
on lymphocytes and some other cell types, but their physiologic was recently identified as mitoferrin (also known as SLC25A37), a
function has not been fully defined.7 Ferritin is also the precursor to transmembrane protein that plays a critical role in supplying iron to
hemosiderin, a heterogeneous aggregate of iron, lysosomal compo- ferrochelatase for insertion into protoporphyrin IX. Mitoferrin was
nents, and other products of intracellular digestion.8 originally discovered in yeast (called MRS3/MRS416) and in a
Submitted December 13, 2007; accepted February 19, 2008; DOI © 2008 by The American Society of Hematology
10.1182/blood-2007-12-077388.
BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 219

220 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2
Figure 1. Overview of iron homeostasis. The central

portion of the figure depicts the flow of iron into the body
(through the small intestine), to transferrin (Tf), to the
major site of utilization (the erythroid bone marrow), to
circulating erythrocytes, to tissue macrophages that
phagocytose senescent erythrocytes and recycle iron
(spleen), to storage in hepatocytes, and back to TF
through mobilization of iron stores. Cellular iron trans-
port is described in detail in the text and shown in
schematic form on the outside edges of this figure.
(A) Nonheme iron transport across an intestinal entero-
cyte. (B) Erythrophagocytosis and iron recycling in a
tissue macrophage. The aqua oval in the cytoplasm
represents a storage depot for ferroportin protein within
the cell. (C) Hepatocyte iron transport, with arrows
indicating that neither import nor export is well under-
stood. (D) Iron uptake through the transferrin cycle in
the erythoblast. Illustration by Kenneth Probst.
mutant zebrafish.17 Interestingly, mutations in mitoferrin result in a indicated that the UTR sequences could form stable RNA hairpins
clinical disorder that is very similar to erythropoietic protoporphy- with a characteristic secondary structure, termed iron responsive
ria caused by ferrochelatase mutations.17 (or regulatory) elements (IREs).24 Soon afterward it was shown that
Although many tissues express TFR1 at low levels, relatively cytoplasmic proteins, now known as iron regulatory proteins (IRPs,
few cell types are strictly dependent on the transferrin cycle for iron formerly IREBPs), recognize and bind to the IREs.25-28
uptake. Targeted disruption of the Tfr1 gene in mice demonstrated The 2 known IRPs share sequence homology but have distinc-
that most tissues develop normally without Tfr1, but erythroid tive properties. At the time of its discovery, IRP1 was recognized to
precursors, early lymphoid cells, and neuroepithelial cells require bear strong similarity to aconitase, a mitochondrial enzyme of the
Tfr1 for differentiation.18,19 The likely role of TFR1 in erythropoi- tricarboxylic acid cycle. Remarkably, IRP1 also has aconitase
esis is obvious—the transferrin cycle serves to concentrate iron in
activity, making it a prime candidate for a previously described
the vicinity of DMT1 to maximize iron assimilation for hemoglo-
cytoplasmic aconitase.29,30 But the aconitase and IRE-binding
bin production. However, it is less clear why lymphopoiesis and
activities are mutually exclusive, providing a clue to a clever
neurodevelopment should require TFR1.
regulatory switch. Similar to a number of other iron-containing
In the past it was assumed that iron assimilated by erythroid
precursors was incorporated into hemoglobin, remaining within the proteins, IRP1 incorporates an iron-sulfur cluster (4Fe•4S). The
cells until erythrocyte senescence. Recently, however, Quigley and iron-sulfur cluster forms when iron is abundant, but disassembles
colleagues20 have described a heme exporter, FLVCR, which when iron is scarce. Haile and Rouault showed that the aconitase
appears to be necessary for normal erythroid development. They activity of IRP1 is present only when the iron-sulfur cluster is
hypothesize that erythroblasts need to have a pop-off valve for complete; when it is not, IRP1 acts as an RNA binding protein,
extra heme to avoid its toxicity. Targeted disruption of the mouse recognizing IREs.31 IRP2, on the other hand, does not incorporate
gene encoding FLVCR demonstrated the importance of this protein an iron-sulfur cluster. Rather, its activity is regulated at the level of
in vivo.21 FLVCR-null mice had a failure of definitive erythropoi- protein stability. Under low iron conditions IRP2 accumulates, but
esis, resulting in fetal demise. Interestingly, the fetuses had when iron is abundant it triggers IRP2 degradation.32-36 It is still not
craniofacial and limb deformities suggestive of Diamond-Blackfan entirely clear why it is necessary to have 2 IRPs, but recent observations
anemia. When the FLVCR gene was inactivated after birth the suggest that the 2 may respond differently over the physiologically
animals developed severe, macrocytic anemia, implying that heme relevant range of oxygen tensions.37 They may also have somewhat
export is important for normal erythropoiesis. different target selectivity among IRE-containing mRNAs.
The ferritin IRE is located just upstream of the start codon for
Regulation of intracellular iron homeostasis protein translation. Muckenthaler and colleagues showed that IRP
Intracellular iron homeostasis is maintained, at least in part, binding sterically blocks recruitment of the small ribosomal
through a very elegant posttranscriptional regulatory mechanism. subunit to the initiation complex, thus preventing translation.38 As a
In 1987, investigators observed that conserved sequences in the result, ferritin protein production is abrogated under low iron
5⬘ untranslated regions (UTRs) of both H- and L-ferritin mRNAs circumstances when the small amount of intracellular iron is
were needed to control a ready but quiescent pool of ferritin mRNA needed for cellular functions. On the other hand, when iron is
in the cell, which could quickly be mobilized to produce ferritin abundant, translational repression is relieved and newly made
protein when iron was abundant.22,23 Thermodynamic predictions ferritin subunits assemble to provide iron storage capacity.
BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 221
The IRE/IRP regulatory system is also used to control expres- fingerlike villi that protrude into the intestinal lumen to maximize
sion of other proteins. The best studied is TFR1, which has multiple absorptive surface area. Each individual absorptive cell, or entero-
IREs in the 3⬘ UTR of its mRNA.39 In this case, IRP regulation cyte, has a microvillous brush border at the apical (luminal)
operates in a very different fashion. Under low iron conditions, IRP surface. Most dietary nonheme iron is in the ferric (Fe3⫹) form. It
binding has no direct effect on translation, but rather it protects the must be reduced to ferrous (Fe2⫹) iron, either chemically or
TFR1 mRNA from endonucleolytic cleavage and consequent through the action of a brush border ferrireductase such as
degradation. When iron is abundant, nucleases attack A-U rich mRNA duodenal cytochrome B (CYBRD1, also known as DCYTB), a
sequences adjacent to the IREs and destabilize TFR1 mRNA. Thus, cytochrome B561 homolog that may use ascorbic acid as a cofactor.53
more TFR1 can be produced when cells are in need of iron, but TFR1 CYBRD1 was one of 2 iron transport–related molecules discovered by
expression is interrupted when cells are iron replete. McKie through a very productive RNA subtraction approach.53,54
Other mRNAs encoding important proteins of iron metabolism Surprisingly, although Cybrd1 expression is markedly induced in
have been shown to have 5⬘ IREs (eg, ferroportin, aminolevulinic iron-deficient animals, targeted disruption of the murine Cybrd1 gene
acid synthase) or 3⬘ IREs (eg, DMT1), though their regulation by was not associated with any apparent phenotype in mice fed standard
the IRE/IRP system has not been thoroughly studied.40 chow.55 Members of the STEAP ferrireductase family are also expressed
Perhaps surprisingly, targeted disruption of the IRP1 gene in in the intestine.56 While they are good candidates for enzymatic
mice produces no apparent phenotypic abnormalities.41 In contrast, ferrireductases at the brush border, the roles of CYBRD1 and STEAPs
targeted disruption of IRP2 leads to a disorder of iron homeostasis in intestinal iron absorption remain uncertain.
characterized by microcytic, hypochromic anemia,42,43 and, at least Fe2⫹ iron enters absorptive enterocytes through DMT1, the
in one laboratory, a late onset neurodegenerative disorder.42,44,45 same iron transporter used for endosomal transfer in the transferrin
When genes encoding both proteins are inactivated, the compound cycle. The intestinal form of DMT1 is produced from a different
mutant mice die early in embryonic development, establishing the mRNA splice isoform, resulting in an alternate C-terminus of the
overall importance of these proteins in vivo. protein.57,58 Intestinal DMT1 is primarily localized to the apical
Spontaneous IRE mutations have been described in human membrane and to subapical endosomes.59 Protons necessary for
patients and in mice.46-48 Beaumont and colleagues48 showed that metal cotransport are provided by gastric acid flowing into the
disruption of the L-ferritin IRE results in hyperferritinemia-cataract proximal portion of the duodenum where DMT1 is most highly
disease, with prominent ocular findings and elevated serum ferritin expressed and likely most active. The requirement for proton
but no evidence of disturbed iron homeostasis. Disruption of the cotransport explains why treatment with antacids or H2 histamine
H-ferritin IRE in one Japanese family was associated with a blockers interferes with iron absorption. DMT1 expression is
familial iron overload disorder.49 Interestingly, a mutation that dramatically induced in iron deficiency,13 and possibly regulated at
prevents formation of the mouse ferroportin IRE causes an unusual a posttranscriptional level by a 3⬘ IRE present in the splice isoform
and complex disorder of iron homeostasis, underscoring the expressed in intestine.57 DMT1 may also serve as a physiologically
significance of this IRE in vivo.50 significant portal of entry for other divalent metal cations including
Mn2⫹, Co2⫹, Zn2⫹, Cu2⫹, and Pb2⫹, though its importance has only
Intestinal iron absorption
been definitively established for Fe2⫹ in vivo.13
In nontransfused individuals, iron enters the body exclusively The sole mammalian homolog of DMT1, designated NRAMP1
through the diet. Because there is no regulated excretion of iron for natural resistance associated macrophage protein 1, was identi-
through the liver or kidneys, iron balance is primarily controlled at fied by Vidal et al through positional cloning of a mouse locus
the level of intestinal absorption. Elegant ferrokinetic studies involved in host defense against intracellular pathogens in mouse
carried out in the middle of the last century gave important macrophages.60 NRAMP1 is expressed in phagosomes of profes-
physiologic insights into human iron absorption and distribution51 sional phagocytes.61 After DMT1 was shown to serve as a
but a molecular understanding of iron absorption came decades transmembrane metal transporter, functional studies indicated that
later (and is still not complete). When we and others began efforts NRAMP1 had similar activity.62 It has bacteriostatic but not bacterio-
to find intestinal iron transporters in the mid-1990s the available cidal activity, presumably because it acts to deplete metals from the
clues were not particularly helpful: (1) the transferrin cycle was phagosomes in which microorganisms replicate, thus depriving them of
known to have no direct role in intestinal iron absorption, iron and/or manganese. Homologous proteins in yeast,63 flies,64 and
(2) mammalian iron transport appeared to be mechanistically zebrafish65 also transport iron and similar divalent cations.
distinct from that of bacteria and single-celled eukaryotes, and Targeted disruption of the murine gene encoding DMT1 con-
(3) ATPase copper transporters, discovered several years earlier, firmed that DMT1 is the primary transmembrane iron transporter
showed no affinity for iron. Protein purification had been attempted bringing dietary nonheme iron into intestinal epithelial cells and
for decades without success. In spite of these obstacles and entirely mediating iron uptake through the transferrin cycle in erythroid
by chance, the first mammalian transmembrane iron transporter precursors.66 Surprisingly, however, most other cell types do not
was discovered simultaneously in 2 laboratories, located within a appear to require DMT1 for iron uptake. This suggests that other
city block of each other in Boston, using singularly modern transmembrane iron importers exist. Studies of non–transferrin
techniques.12,13 Ours was one of those labs, and this marked our bound iron uptake by cultured cells support this conclusion.67-72
entrée into the field of iron biology. Our approach was to take However, aside from L-type calcium channels, which have some
advantage of well-characterized mouse strains that carried sponta- iron carrying capability,73 no compelling candidates have been identified
neous mutations perturbing iron homeostasis. At the time, 6 strains that transport iron atoms directly into cells. There is a siderophore-like
had been identified; all are now understood in molecular detail.14 iron uptake pathway mediated by lipocalin-2 (also called NGAL, 24p3)
One in particular, microcytic anemia (mk), had been carefully but its physiologic role is not fully worked out.74-76
studied and shown to have a defect in intestinal iron absorption.52 Once inside the intestinal epithelial cell, iron has at least
Iron absorption takes place in the proximal portion of the 2 possible fates. A portion remains in the cell for use or storage.
duodenum (Figure 1), where polarized cells are arranged in This iron is never absorbed into the body; rather, it is lost when
Table 1. Genes involved in inherited human iron disorders

Human chromosome Disease (caused by loss-of-function mutations
Protein (gene symbol) 关aliases兴 (map position) Protein function unless otherwise noted)
Ceruloplasmin (CP) 3 (150 Mb) Plasma ferroxidase Aceruloplasminemia184

DMT1 (SLC11A2) 关NRAMP2, DCT1兴 12 (50 Mb) Transmembrane iron transporter (importer) Anemia with hepatic iron overload172
Ferritin H chain (FTH1) 11 (61 Mb) Subunit of iron storage protein; has ferroxidase Iron overload (mutation disrupting iron regulatory
activity element)49
Ferritin L chain (FTL) 19 (54 Mb) Subunit of iron storage protein Hyperferritinemia-cataract syndrome (mutation
disrupting iron regulatory element)48
Ferroportin (SLC40A1) 关IREG1, MTP1兴 2 (190 Mb) Transmembrane iron transporter (exporter) Macrophage-predominant iron overload (loss-of-
function mutations that cause protein mis-
localization)156
Hemochromatosis (gain-of-function mutations that
cause insensitivity to hepcidin)158,159
Frataxin (FXN) 9 (71 Mb) Mitochondrial iron chaperone Friedreich ataxia212
Glutaredoxin 5 (GLRX5) 关GRX5兴 14 (95 Mb) Participates in Fe-S cluster biogenesis Anemia with iron overload and sideroblasts171
Hemojuvelin (HFE2) 关RGMC兴 1 (144 Mb) Bone morphogenetic protein coreceptor Juvenile hemochromatosis138
Hepcidin (HAMP) 关LEAP1兴 19 (40 Mb) Iron regulatory hormone, binds ferroportin to Juvenile hemochromatosis161
cause its inactivation and degradation
HFE (HFE) 关HLA-H兴 6 (26 Mb) Regulates hepcidin expression, mechanism Classic HLA-linked hemochromatosis121
uncertain; interacts with TFR1 and TFR2; may
participate in a signaling complex with TFR2
Mitoferrin (SLC25A37) 8 (23 Mb) Mitochondrial iron import Erythropoietic protoporphyria17
Transferrin (TF) 3 (135 Mb) Plasma iron binding protein, ligand for TFR1 and Atransferrinemia (hypotransferrinemia)178
TFR2
Transferrin receptor-2 (TFR2) 7 (100 Mb) Sensor for diferric transferrin; regulates hepcidin Hemochromatosis213
expression; may participate in a signaling
complex with HFE
enterocytes senesce and are sloughed into the gut lumen. Only iron distribution. Iron deficiency anemia, hemochromatosis, and the anemia
exported across the basolateral membrane of the enterocyte is of chronic disease (also known as the anemia of inflammation) are all
absorbed. The basolateral iron transporter, discovered simulta- common examples of this principle, as will be discussed later. Hence,
neously by 3 labs, is ferroportin (also called IREG1, MTP1, understanding iron homeostasis is critical for understanding these
SLC39A1, and now SLC40A1).54,77,78 Ferroportin is resident on the disorders. Conversely, understanding genetic iron disorders (Table 1)
basolateral membrane, and also found in macrophages involved in has provided important insights into iron homeostasis.
recycling iron from the hemoglobin of effete erythrocytes (Figure Systemic iron homeostasis involves meticulous control of
1). Targeted disruption of the murine ferroportin gene demon- intestinal iron absorption, effective utilization of iron for erythropoi-
strated its importance in both sites.79 esis, efficient recycling of iron from effete erythrocytes, and
Although functional studies are incomplete, ferroportin likely controlled storage of iron by hepatocytes and macrophages (Figure
transports ferrous ion. Transport is facilitated by multicopper 1). Erythroid iron utilization is primarily determined by the efficiency of
ferroxidases including the abundant serum protein ceruloplasmin transferrin cycle assimilation of serum iron. In contrast, intestinal
and its membrane-bound intestinal homolog hephaestin.80-83 Until absorption, iron recycling, and iron storage are controlled systemically
recently, the ferroxidases were thought to be important simply for and coordinately. In this context, we now know that hepcidin, a peptide
oxidizing Fe2⫹ to load it onto transferrin. However, De Domenico hormone produced in the liver, has primary responsibility for modulat-
and colleagues have recently shown that ceruloplasmin is required ing iron availability to meet iron needs.
to maintain cell-surface localization of ferroportin.84 This situation Discovered independently by 3 laboratories and first reported in
is somewhat analogous to iron transport in yeast, where the ferrous 2000 and 2001, hepcidin is a 25-amino-acid protein produced by
iron permease FTR1 (functionally analogous but structurally processing of a larger precursor.90-92 Although it bears resemblance
unrelated to DMT1) requires the multicopper ferroxidase FET3 for to defensin peptides involved in innate immunity, its primary
correct localization on the cell surface.85,86 function appears to be regulation of iron homeostasis through a
Intestinal absorption of nonheme iron is now understood in mechanism that was elegantly elucidated by Kaplan, Nemeth,
some detail, but the absorption of heme iron, primarily derived Ganz, De Domenico, and their coworkers. Hepcidin binds to
from meats, remains poorly understood. A description of a putative cell-surface ferroportin, triggering its tyrosine phosphorylation,
heme importer in 200587 later proved to be incorrect.88 While heme internalization, and ubiquitin-mediated degradation in lyso-
exporter proteins have been described,20,89 it seems likely that most somes.93,94 By removing ferroportin from the plasma membrane,
iron dietary heme iron is liberated from protoporphyrin by heme hepcidin shuts off cellular iron export. This is particularly impor-
oxygenase to enter a common pathway with dietary nonheme iron
tant in the intestine, where inactivation of basolateral ferroportin
before it leaves the absorptive epithelium.
leads to retention of iron in the intestinal epithelium, and in
Regulation of iron homeostasis by hepcidin
iron-recycling macrophages of the reticuloendothelial system,
where inactivation of ferroportin interrupts release of iron recov-
Although its handling is frequently termed iron “metabolism,” iron ered from senescent red cells (Figure 2A). Both events have the
itself is not metabolized in a classical sense. Accordingly, human same consequence—decreased serum iron. Interestingly, the impor-
iron disorders are invariably disorders of iron balance or iron tance of controlling basolateral transfer to effect regulation of
Figure 2. Hepcidin and hemochromatosis. (A) The

activity of hepcidin is depicted, showing ferroportin as a
target both on enterocytes and macrophages. Hepcidin
binds to ferroportin triggering its internalization and
lysosomal degradation. (B) Three classes of hemochro-
matosis disorders all affect the hepcidin/ferroportin
regulatory axis: Class I, defects in the hepcidin gene
(HAMP) preventing production of functional hepcidin;
Class II, defects in HFE, TFR2, or HFE2 genes prevent-
ing normal hepatic regulation of hepcidin expression;
Class III, defects in ferroportin preventing normal regu-
lation by hepcidin. Illustration by Kenneth Probst.
intestinal iron absorption was initially postulated by Crosby and hepcidin in inflammation, through a signaling pathway triggered by
Conrad more than 40 years before the mechanism was elucidated.95 interleukin-6.107,108 The von Hippel-Lindau/hypoxia-inducible transcrip-
Hepcidin is primarily made in hepatocytes, and secreted into tion factor (HIF) system also appears to control hepcidin expression,
the circulation. The liver acts as a clearinghouse for a variety of with HIF1␣ acting as a repressor when it binds to the hepcidin
signals affecting iron homeostasis. Because of its small size, promoter.109 Potential binding sites for C/EBP␣, USF2, HNF4␣, p53
hepcidin is probably filtered by the kidneys on the first pass. It and other widely expressed transcription factors have also been identi-
has been detected and quantitated in urine samples,91,96 and, fied in the hepcidin promoter, but it is not yet clear what roles, if any,
with more difficulty, in serum.97 Its rapid excretion implies that they have in regulation of hepcidin expression in vivo.110-112
most regulation of serum hepcidin levels occurs at the level of Signaling through the bone morphogenetic protein (BMP)/
production. Proteolytic processing of the prohormone is carried SMAD pathway is the most powerful mechanism known to
out by furin in a relatively unregulated manner.98 In contrast, activate hepcidin transcription. This surprising connection between
hepcidin transcription is tightly regulated over a very wide BMPs and hepcidin was initially discovered through 2 independent
dynamic range. avenues of research. In the course of their general studies of
Initially, murine hepcidin mRNA was shown to be elevated in
cellular signaling, Wang and colleagues inactivated the gene
response to iron overload92 and decreased in response to iron
encoding an essential SMAD protein, SMAD4, exclusively in
deficiency.99,100 The functional effects of altered hepcidin expres-
hepatocytes.113 To their surprise, the dominant phenotype that
sion in vivo were apparent when Nicolas, Lesbordes-Brion, and
resulted was severe hemochromatosis, similar to that seen in mice
colleagues showed that inactivation of the hepcidin gene in mice
lacking hepcidin. In parallel, Babitt and colleagues studied hemoju-
was associated with severe iron overload.101,102 Conversely, trans-
velin, a protein mutated in patients with severe, early onset
genic overexpression of hepcidin resulted in iron deficiency.103,104
In addition, the amount of hepcidin mRNA in liver cells is “juvenile hemochromatosis.”114 They showed that hemojuvelin
decreased in response to hypoxia and ineffective erythropoiesis acts as a BMP coreceptor to stimulate hepcidin transcription. Both
(overlapping with the response to iron deficiency)99,105 and induced groups demonstrated that treatment of hepatic cells with BMPs
in response to treatment with lipopolysaccharide or by inflamma- stimulated hepcidin expression, in a manner dependent on the
tion of other etiologies.92,99 These responses all make sense: when presence of SMAD4,113 BMPs, and hemojuvelin.114
erythropoiesis needs to accelerate, interruption of hepcidin expres- It seems likely that activated SMADs bind directly to the
sion results in increased iron availability. In contrast, induction of hepcidin promoter in response to BMP signaling. However, in
hepcidin in inflammation and consequent iron sequestration aug- contrast to some other transcription factors, consensus sites for
ments innate immune defenses against invading pathogens.106 SMAD binding are highly variable and difficult to predict by
Current information about the hepcidin promoter indicates that sequence analysis alone. Truksa et al have localized putative
it is relatively compact, as it must be to avoid encroaching on a BMP-responsive elements in the hepcidin promoter,115 but it is still
closely neighboring gene encoding USF2. The most proximal uncertain exactly how BMP transcriptional regulation occurs.
region is highly conserved across mammalian species.107 A consen- Nonetheless, BMP treatment is a potent stimulus for hepcidin
sus STAT3 binding site has been shown to mediate the induction of expression both in cultured cells113,114,116,117 and in animals.117
Hemochromatosis increase in response to iron-saturated transferrin.151,153-155 Taking

this into account, we have proposed a model in which TFR2 escorts
Our understanding of hepcidin regulation has been greatly en- HFE away from TFR1 when the serum iron level (reflected in the
hanced through efforts to understand hemochromatosis, a genetic transferrin saturation) is elevated.149,150 The implication of this
iron overload disorder. Described as “bronze diabetes” by Trous- model is that HFE and TFR2 collaborate in a signaling complex
seau in 1865,118 hemochromatosis was not known to be an iron that acts to augment hepcidin expression. These proteins may be
disorder until well into the 20th century.119 It was one of the first part of a larger BMP signaling complex along with hemojuvelin
genetic diseases to be linked to a discrete chromosomal position, (P.J. Schmidt, F.W. Huang, and N.C.A., unpublished results).
through the groundbreaking work of Simon, an astute French Hemochromatosis can also result from mutations in the gene
physician-scientist who found that hemochromatosis patients were encoding ferroportin, the target of hepcidin activity. The first
disproportionately likely to have particular HLA haplotypes.120 mutations in ferroportin were discovered simultaneously by Mon-
Two decades later that insight led to the identification of HFE tosi et al156 and Njajou et al157 in families with iron overload
(originally called HLA-H), the gene mutated in the large majority of segregating in an autosomal dominant pattern. Many other muta-
patients with hemochromatosis.121 The positional cloning of HFE tions have been reported subsequently. Initially there was disagree-
by a now-defunct biotechnology company was a tour de force, and ment about the clinical presentation: some patients seemed to have
one of the landmark accomplishments of the middle years of the macrophage-predominant iron loading and occasional anemia, while
human genome project. others had clinical features indistinguishable from HFE hemochromato-
As is often the case, however, the situation is more complex sis. Strikingly, all ferroportin mutations caused missense changes, rather
than originally appreciated. We now know that HFE is one of than truncations or frameshifts. Furthermore, knockout mice heterozy-
several genes that can be mutated in hemochromatosis. Further- gous for a null ferroportin allele had no significant iron phenotype, and
more, penetrance of HFE hemochromatosis is incomplete, and only did not seem to model the human disease.79
a fraction of affected patients have clinical disease, presumably due to These issues were resolved by the discovery that there are
both genetic and environmental modifiers.122 Several modifier gene 2 broad categories of ferroportin mutations.158,159 Missense muta-
candidates have been explored and, in some cases, verified.123-135 Not tions that affected the subcellular localization or transporter
surprisingly, heterozygous mutations in other hemochromatosis- function of ferroportin (“loss-of-function”) were associated with
associated genes can exacerbate the clinical course for patients who macrophage iron loading but few, if any, sequelae resembling
are also homozygous for HFE mutations. classical hemochromatosis. In contrast, missense mutations that
Like hemojuvelin, both HFE and transferrin receptor-2 (TFR2, rendered ferroportin insensitive to regulation by hepcidin (“gain-of-
another hemochromatosis-associated protein) are inferred to be function”) caused hemochromatosis. The fact that both types of
involved in regulation of hepcidin expression. Human patients with mutations have autosomal dominant patterns of clinical expression
mutations in the genes encoding hemojuvelin, HFE, or TFR2 have can be reconciled by the conclusion that ferroportin polypeptides
inappropriately low urinary hepcidin levels for their overall body assemble into homo-multimers.158 Recently, a mouse model of the
iron status.136-139 As a consequence, intestinal iron absorption and disease associated with loss-of-function ferroportin mutations,
macrophage iron release are not properly controlled, leading to iron flatiron, was identified through a positional cloning effort.160
overload, increased serum iron, and iron deposition in the liver, There are not many precedents for inactivating and activating
heart, and endocrine tissues. Similarly, mouse models of hemochro- mutations in one gene causing 2 different diseases. Accordingly,
matosis developed through targeted disruption of any of these there is no consensus yet on nomenclature for these disorders. It has
3 genes have diminished hepcidin mRNA in their livers.140-144 been suggested that the condition associated with loss-of-function
While this is strong evidence that all 3 proteins are involved in mutations should be called “ferroportin disease” and the condition
hepcidin regulation, the roles of HFE and TFR2 are not as well associated with gain-of-function mutations should be called type IV
understood as that of hemojuvelin. hemochromatosis. The classification scheme is blurred, however, by the
HFE is an atypical major histocompatibility class I–like mole- fact that some mutations appear to have features of both types.
cule that forms a heterodimer with ␤2-microglobulin but is Thus, based on our current understanding, the molecular
incapable of binding a small peptide.145 Soon after its discovery, pathogenesis of hemochromatosis can be divided into 3 classes
HFE was shown to interact with TFR1 to form a protein-protein (Figure 2B). First, mutations in the hepcidin gene itself (called
complex.145-147 Initially, its role in iron homeostasis was thought to HAMP) cause hemochromatosis by preventing the production of
involve perturbation of the transferrin cycle, either in hepatocytes or in functional hepcidin protein.161 Second, mutations in the genes
intestinal epithelial cells (reviewed in Roy and Enns148). However, more encoding HFE (HFE), TFR2 (TFR2), and hemojuvelin (HFE2)
recent results suggest a different scenario: that TFR1 regulates HFE inactivate signaling pathways that normally up-regulate hepcidin
activity and inhibits HFE by sequestering it.149 Because TF and HFE expression. Finally, mutations in the gene encoding ferroportin
compete for binding to TFR1, displacement of HFE from TFR1 by TF (SLC40A1) can cause hemochromatosis by rendering the trans-
may be a means to activate HFE to signal through an as-yet-unknown porter insensitive to hepcidin regulation.158,162
mechanism to increase hepcidin transcription.
Iron deficiency anemia
TFR2 probably fits into this scenario in some intimate way.
Mutations in TFR2 are much less common than mutations in HFE, Iron deficiency anemia continues to be a major public health
but the clinical disease can be indistinguishable.133 Like TFR1, problem worldwide, with an estimated 3 billion people affected.
TFR2 interacts with HFE to form a stable protein complex.150 Arguably, the first thorough descriptions of iron deficiency and its
However, as shown by Chen and Enns, HFE does not bind to treatment involved chlorosis, a perplexing condition due at least in
homologous portions of TFR1 and TFR2.151 Although TFR2 is large part to iron deficiency anemia that was diagnosed between the
43% homologous to TFR1 in its extracellular domain, it does not Middle Ages and the end of the Victorian era in the 1920s. It is
take up diferric-TF efficiently.152 Rather, its primary function remarkable to think that some of the founders of ASH may have
seems to be to interpret body iron status. Amounts of TFR2 protein seen patients with this disorder. Sydenham, in 1681, recognized
that chlorosis could be cured by “the effects of steel.”163 Ferrous high levels in the liver. The mechanism through which matriptase-2
sulfate pills, still a mainstay for treatment of iron deficiency, have regulates hepcidin expression has not yet been determined. We
been in use for nearly 2 centuries.164 The efficacy of iron treatment asked whether mutations in the human ortholog, TMPRSS6, might
was formally established in a classic experiment carried out by cause IRIDA. We had been collecting DNA samples from IRIDA
Castle. He proved that the active substance was iron when he patients since I first saw a young boy with this disorder in 1996.
administered parenteral iron and showed a proportionate rise in Every patient who fit our strict criteria for IRIDA carried inactivat-
hemoglobin in patients with hypochromic anemia.165 ing mutations in TMPRSS6 that could explain the disease.190,192
The vast majority of cases of iron deficiency are acquired, Further studies will be needed to determine the prevalence of this
resulting from blood loss (eg, from intestinal parasitosis), from rare disorder, and to evaluate the possibility that less severe
insufficient dietary iron intake, or both. Young children and mutations increase susceptibility to common, acquired iron defi-
menstruating women are disproportionately affected because their ciency anemia.
iron status is marginal to begin with. Recently it was rediscovered
that infection with H pylori, even in the absence of significant
Anemia of chronic disease
bleeding, can lead to profound iron deficiency anemia that is poorly
responsive to oral iron therapy. This disorder is typically seen in The anemia of chronic disease (also called anemia of inflamma-
young women, is associated with gastric atrophy, and can be tion) is an acquired disorder of iron homeostasis (reviewed in Roy
associated with other autoimmune phenomena.166,167 As pointed and Andrews193). A common explanation for anemia in chronically
out by Hershko and colleagues,168 this constellation of findings was ill patients, anemia of chronic disease was largely a diagnosis of
reported a century ago by Faber169 and further described by exclusion in the past. Elegantly described by Cartwright in a classic
Wintrobe and Beebe.170 Eradication of H pylori infection can lead review,194 this condition may be associated with infection, malig-
to correction of the anemia.167 nancy, organ failure, trauma, or other causes of inflammation. The
It is now recognized that rare genetic defects can also cause iron anemia is typically mild to moderate, and erythrocytes may not
deficiency anemia. Mutations in the genes encoding DMT1 show any stigmata of iron deficiency. But the underlying iron
(SLC11A2) and glutaredoxin 5 (GLRX5) are associated with etiology is evident: macrophages that normally recycle iron are
autosomal recessive hypochromic, microcytic anemia.171,172 Inter- found to sequester it, intestinal iron absorption is interrupted, and
estingly, the clinical phenotype of patients with DMT1 mutations erythroid precursors respond very rapidly when iron-transferrin is
differs slightly from the corresponding mouse model, mk.12 The made available. An association with proinflammatory cytokines
human patients have similar blood films and erythrocyte abnormali- has been suspected for some time,195 but was not well understood
ties, but also have hepatic iron overload that is not fully explained until recently.
by their transfusion histories.172-176 Perhaps less surprising, the Studying an unusual group of patients, we developed an
clinical phenotype of a unique patient carrying a GLRX5 mutation hypothesis to explain the anemia of chronic disease, which has
also differs somewhat from an earlier animal model with a deletion subsequently been validated by others.196 Treated survivors of
of that gene, the shiraz zebrafish.177 glycogen storage disease type 1a frequently develop benign hepatic
Two forms of genetic iron deficiency anemia are associated with adenomas in early adulthood. With Weinstein, Roy, and colleagues,
iron overload outside of the erythron. Deficiency of serum trans- we observed that these patients also develop anemia resembling the
ferrin, due to mutations in the TF gene itself,178,179 interrupts iron anemia of chronic disease, the severity of which correlates directly
delivery to erythroid precursors, triggering a massive but futile with the extent of tumor burden.100 We found that the hepatocyte-
increase in intestinal iron absorption and consequent tissue iron like cells of the adenomas expressed very high levels of hepcidin100
deposition. This disorder, hypotransferrinemia (also called atrans- and speculated that our results could be generalized—that induc-
ferrinemia), has been observed in both human patients and in tion of hepcidin expression in response to inflammation might
mice.180-183 Through a different mechanism, deficiency of another explain the anemia of chronic disease. Subsequent studies by
major plasma protein, cerulopasmin, also causes mild iron defi- Nemeth and colleagues96,197 strongly supported our hypothesis, and
ciency anemia associated with iron accumulation in the liver and it is now widely accepted.
brain.184 As reported by Harris and colleagues,184 iron deficiency In a sense, anemia of chronic disease is the phenotypic opposite
results from lack of ferroxidase activity needed to mobilize iron of hemochromatosis. Expression of hepcidin that is inappropriately
from storage. Although both of these disorders are rare, each can be high for body iron status results in interruption of intestinal iron
confused with hemochromatosis if the entire clinical picture is not absorption and iron recycling. Consequently, decreased serum iron
taken into account. is available for erythropoiesis. Accordingly, Roy and colleagues
We and others have observed that some patients have congeni- have developed a transgenic mouse model expressing hepcidin,
tal, iron-refractory, iron-deficiency anemia (IRIDA) that cannot be which shows that most consistent features of the anemia of chronic
explained by mutations in the genes encoding DMT1, GLRX5, TF, disease can be attributed to increased hepcidin expression.104 Our
or ceruloplasmin.185-190 These individuals appear to have a defect in recent discovery that IRIDA is also caused by inappropriately high
cellular iron export,191 but the disorder has an autosomal recessive hepcidin expression suggests that IRIDA and the anemia of chronic
pattern of inheritance and no mutations have been detected in disease should have common clinical features. While this is true in
ferroportin or in the regulatory regions of the hepcidin gene.190 An some regards, one striking difference is that IRIDA is associated
important clue to the etiology of IRIDA came recently when Ernest with severe microcytosis, whereas the anemia of chronic disease is
Beutler and his son Bruce identified Tmprss6, encoding matriptase-2, typically normocytic. Mice expressing a hepcidin transgene are
as the gene mutated in a novel mouse mutant, Mask.192 microcytic, similar to IRIDA.104 I speculate that the normocytic
In addition to a bizarre hair pattern that led to the strain name, erythrocytes in the anemia of chronic disease result from the
Mask mice have severe iron deficiency anemia attributable to combination of iron insufficiency and an as-yet-unexplained ten-
elevated hepcidin expression. Matriptase-2 is a type II transmem- dency to macrocytosis. For example, it is plausible that folate
brane serine protease of unknown function, which is expressed at homeostasis is also perturbed in response to inflammation.
Conclusions and future directions manipulation of iron loss through the gut epithelium or through the
kidneys are 2 possible approaches.
Iron biology is a vast field and, necessarily, there are important
Our understanding of the anemia of chronic disease has
areas that I have neglected in this review. These include mitochon-
progressed enormously over the past few years. As we refine our
drial iron metabolism, heme metabolism, brain iron accumulation
understanding of hepcidin-related manifestations and other manifes-
in neurodegenerative disorders, Fe•S cluster formation, therapeutic
tations, it should become possible to stratify this disorder according
chelation, classical ferrokinetics, microbial iron metabolism, and
to causes and effects. Undoubtedly there will be new treatment
others. Focusing on physiology more than biochemistry, I have not
strategies based on our understanding of the biology of the anemia
given due attention to recent structural characterizations of TFR1,
of chronic disease. It is quite likely that this understanding will also
HFE, or IRP1 alone and in interactions with the molecules they
lead to a better appreciation of the molecular pathology of the
bind to.145,198-200 My choice of topics should not be viewed as a
anemia of aging.
judgment of what is most important; rather, it simply reflects my
A better understanding of iron homeostasis may also enhance
areas of expertise and a focus on diseases that have only recently
treatments for other disorders. We still have much to learn about
become understood. Looking ahead, it is fun to speculate on what
iron homeostasis in solid tumors, and about possible roles for
we will learn in the next round of discoveries in iron biology. In my
lipocalin-2 and its receptor76 in malignant transformation. Iron
opinion, any wish list has to focus on the iron disorders that affect
deposition is a hallmark of many neurodegenerative disorders,211
our patients—in the final analysis, they are why most of us have
and manipulating iron distribution in the central nervous system
chosen to work in this area.
may become an important therapeutic approach. Similarly, iron-
First, I think there will be a new surge of interest in iron
depleting strategies may someday be used to alter innate immunity
deficiency. We are in an unprecedented position to understand the
and to enhance host defense against invading pathogens. I would
genome/environment interactions that make some people particu-
venture that a better understanding of iron biology will reap
larly susceptible to iron deficiency. Among these interactions, we
benefits for virtually every field of medicine, keeping our students
should soon understand why infection with H pylori causes
and fellows busy for decades to come.
profound iron deficiency that cannot be explained by blood loss or
failed iron absorption. We will understand the “erythroid regulator”
that communicates body iron needs to liver hepatocytes producing
hepcidin, allowing for mobilization of all available iron when Acknowledgments
erythropoiesis accelerates. New understanding of iron biology may
have therapeutic benefits as well. Perhaps it will lead to novel I would like to thank colleagues in the field of iron biology who
methods for oral iron repletion, allowing it to be accomplished in generously welcomed me into their world 12 years ago, and in
days, rather than months. If this becomes possible, it will have particular Mark Fleming, a long-term collaborator who gave me
enormous implications around the globe. Finally, pica, an enig- a strong push to get into it. I feel quite privileged to work in a
matic but almost pathognomonic symptom of severe iron defi- field that has benefited so much from the diversity of its
ciency, may provide clues to help us understand the intricate links investigators: iron biology is a truly international pursuit that
between nutrition and behavior. has developed from the efforts of scientists in Europe, Australia,
Second, we still have more to learn about primary iron Asia, Africa, and the Americas; fruitful approaches have ranged
overload disorders. Mutations in the 5 genes currently associ- from traditional biochemistry to modern mouse genetics to
ated with hemochromatosis probably do not account for all clinical measurements and everything in between. Like me,
patients with the disease. There is likely to be at least one many others have stumbled into iron biology, often proclaiming
additional gene yet to be identified. Even when the list is that they will just do a bit of work and then return to their home
complete, we will need a better understanding of genetic field, but almost always deciding to stay. Their fresh perspec-
modifiers to fully understand why clinical presentations vary tives have made the field even more exciting, and more
dramatically. Knowledge of the full genetic landscape of welcoming to young scientists. Finally, I have had far more than
hemochromatosis may lead to new approaches to replace my share of luck in working with outstanding students, postdoc-
blood-letting (phlebotomy), a treatment that was introduced toral fellows, and technicians in my own laboratory. I owe them
almost a decade before ASH was founded. Because phlebotomy a great deal for having made this journey so rewarding and so
is cheap, easy, safe, and effective, it will be difficult to supplant. much fun.
But considering how responsive hepcidin expression is to a The work in my laboratory is currently supported by National
variety of stimuli, it is quite possible that a safe and effective Institutes of Health R01 grants HL051057, DK066373, and
drug currently used for a different purpose might turn out to DK053813, as well as a grant from the Roche Foundation for
have unexpected hepcidin-inducing activity, solving the prob- Anemia Research.
lem. Finally, although we have made great strides in understand-
ing hemochromatosis in individuals of European descent, we
remain largely ignorant of the causes and manifestations of iron
overload in individuals of African descent, in spite of the Authorship
apparent prevalence of the condition in that population.201-210
Transfusional iron overload is relatively well understood. In my Contribution: N.C.A. wrote the paper.
opinion, the goal in coming years should be to use biology, rather Conflict-of-interest disclosure: The author declares no compet-
than chemistry, to treat it. By that I mean that detailed knowledge of ing financial interests.
iron homeostasis will suggest new therapeutic opportunities to Correspondence: Nancy C. Andrews, Duke University School
deliberately remove iron from the body, even though there is no of Medicine, DUMC 2927, Durham, NC 27710; e-mail:
natural excretion pathway through the liver or kidneys. Deliberate nancy.andrews@duke.edu.
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tion identifies TMPRSS6 as an essential suppres- iron overload persists in rural sub-Saharan Africa. TFR2 is mutated in a new type of haemochromatosis
sor of hepcidin gene expression, required for nor- Lancet. 1986;1:1310-1313. mapping to 7q22. Nat Genet. 2000;25:14-15.
My first exposure to hematology was “Hemo the Magnificent,” a 1957 education film from Bell Sci-
ence that made blood come alive (literally). Hemo was half red and half blue. My earliest hematol-
ogy experiments, in high school, were with blue blood. I was fascinated by the fact that the
hemocyanin-containing blood of the horseshoe crab coagulates when exposed to tiny amounts of
endotoxin. I convinced some friends to drive an old VW bus from Syracuse to Cape Cod to collect
the creatures. I returned with 30 horseshoe crabs, which I kept in saltwater tanks in my bedroom.
A biology professor at Syracuse University allowed me to work in her lab to try to figure out why
the crab blood clotted. Several days a week I walked to the university after school, carrying my
research subject in a plastic bucket. I got scooped on the project, but did learn some basic lab
techniques that have stuck with me 35 years later.
I went to Yale College hoping to become a scientist. I was lucky to meet Joan Steitz, then a young
professor at the forefront of the emerging field of molecular biology. Her lab was a bold and excit-
ing place. There I witnessed the discovery of snurps—ribonucleoprotein particles that are now
known to play several fundamental roles in cell biology. Snurps were revealed using sera from
patients with autoimmune disorders to immunoprecipitate autoantigens from cell lysates. It was a
very clever approach, and it taught me how major advances could come from looking at human
disease (and blood) in a novel way—a lesson that has served me well.
I probably would not have gone to medical school if it weren’t for the MD-PhD students who or-
bited around Joan’s lab. I ended up in the MD-PhD program at Harvard and did my PhD thesis
work with Nobel laureate David Baltimore at MIT. Hematology and cancer were big at MIT at that
time. Both Sam Lux and David Nathan passed through on mini-sabbaticals, working with Harvey
Lodish, David Housman, and others. Once again I was in the right place at the right time; the MIT
Biology Department was a remarkable incubator for scientific talent in the early 1980s. An as-
tounding number of future scientific leaders spent time there as students, postdocs, or visiting
scientists. I was in the Baltimore lab when the Whitehead Institute was born, with David as its
Nancy C. Andrews
founding director. It was fun to watch, and it probably inspired my own foray into administration
2 decades later.
I formally entered hematology in 1989 as a fellow at Children’s Hospital Boston and Dana-Farber Cancer Institute. I was interested in red cells and chose
Stuart Orkin’s lab for my fellowship research. There I took advantage of my previous biochemistry experience (dating back to the horseshoe crab days)
to purify and clone a hematopoietic-specific transcription factor, NF-E2. It was a huge job, requiring thousands of liters of cultured cells to get enough
material, but it worked in the end.
I might have continued working on NF-E2 if it weren’t for several circumstances that lured me into iron biology. Most important among these were meet-
ing Mark Fleming, then a Harvard medical student, and becoming an investigator of the Howard Hughes Medical Institute. Mark, now a long-time collabo-
rator, convinced me to share his curiosity about the pathophysiology of hemochromatosis. HHMI provided the unrestricted funding I needed to move into
a completely new area of science.
Although I have less time for the lab now than I once did, I still love science. I’ve been fortunate to have helped make a few important discoveries over the
years. But even more satisfying, I’ve had a part in teaching, advising, and mentoring an amazing group of students, postdocs, and technicians. It is great
fun to watch them develop their own careers and follow their own imaginations.
2008 112: 219-230

doi:10.1182/blood-2007-12-077388
Forging a field: the golden age of iron biology

Nancy C. Andrews
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From www.bloodjournal.org by guest on December 21, 2017. For personal use only.

ASH 50th anniversary review

Forging a field: the golden age of iron biology

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 219

220 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

Figure 1. Overview of iron homeostasis. The central

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 221

222 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

Table 1. Genes involved in inherited human iron disorders

Ceruloplasmin (CP) 3 (150 Mb) Plasma ferroxidase Aceruloplasminemia184

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 223

Figure 2. Hepcidin and hemochromatosis. (A) The

224 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

Hemochromatosis increase in response to iron-saturated transferrin.151,153-155 Taking

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 225

226 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 227

228 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2 IRON BIOLOGY 229

230 ANDREWS BLOOD, 15 JULY 2008 䡠 VOLUME 112, NUMBER 2

2008 112: 219-230

Forging a field: the golden age of iron biology

Updated information and services can be found at:

Information about ordering reprints may be found online at:

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