Muchowska KB, Varma SJ, Moran J
Nature. 2019 May;569(7754):104-107. PDF
Recommended by Dr. Paolo Arosio
Nature. 2019 May;569(7754):47-49.PDF
Muchowska KB, Varma SJ, Moran J
Nature. 2019 May;569(7754):104-107. PDF
Recommended by Dr. Paolo Arosio
Nature. 2019 May;569(7754):47-49.PDF
A commentary by Elizabeta Nemeth
Bessman et al. Dendritic cell-derived hepcidin promotes intestinal repair. Science. April 10, 2020. https://www.ncbi.nlm.nih.gov/pubmed/32273468
The liver-derived hormone hepcidin regulates systemic iron homeostasis by occluding and causing the degradation of ferroportin on duodenal enterocytes that absorb dietary iron and on macrophages that recycle iron from old red blood cells. In recent years, however, generation of floxed-hepcidin mice has enabled conditional deletion of hepcidin in different cell types, and has revealed tissue-specific roles of the locally-produced hepcidin. Ablation of cardiomyocyte hepcidin led to cardiomyocyte iron deficiency, and contractile and metabolic dysfunction of the heart1. Ablation of hepcidin in macrophages, on the other hand, improved cardiac repair and regeneration in a model of acute myocardial infarction2. Ablation of hepcidin in keratinocytes worsened necrotizing fasciitis by impairing the recruitment of neutrophils3.
In a recent study published in Science by Bessman et al4 (also see the accompanying commentary5), the spectrum of local hepcidin roles was expanded to mucosal healing in a mouse model of inflammatory bowel disease (IBD). Surprisingly, it was the dendritic cells in the intestinal lamina propria of inflamed mice and human IBD patients that had elevated hepcidin expression. Ablation of hepcidin in these antigen-presenting cells in mice worsened the recovery from DSS-induced intestinal damage. Mice lost more weight, had disordered colon tissue architecture and shorter colon length compared to the control animals. Similarly impaired mucosal healing was observed in mice expressing hepcidin-resistant ferroportin in macrophages and neutrophils, suggesting that these cells are the targets of dendritic cell-derived hepcidin.
As to the mechanism by which hepcidin promotes mucosal healing, Bessman et al. show that hepcidin ablation in dendritic cells resulted in altered microbiota composition. This occurred in naïve mice (in the absence of the DSS insult), and in the absence of detectable iron changes in the gut. How the low levels of hepcidin production by dendritic cells in the absence of inflammation affect microbiota remains to be determined. However, fecal microbiota transplantation from the knockouts to germ-free wild-type mice recapitulated the impaired mucosal healing after DSS administration. This was partially attributed to the decreased abundance in the knockouts of the iron-sensitive Bifidobacterium species, which are known to protect the intestinal barrier. The authors hypothesized that in the absence of local hepcidin production during the DSS insult in KO mice, macrophage iron export increases, potentiated by enhanced recycling of RBCs due to local bleeding. This would result in higher extracellular iron concentration, and affect the growth of luminal and tissue-infiltrating bacteria. In support of this hypothesis, systemic administration of the iron chelator DFO improved mucosal healing in dendritic cell hepcidin KOs.
The article raises a number of important questions and therapeutic implications. Can hepcidin mimetics be used to improve mucosal healing in IBD? How does locally derived hepcidin in the absence of inflammation alter microbiota? Does hepcidin derived from dendritic cells play a role in other inflammatory conditions and in other tissues?
Olga Protchenko and Caroline Philpott
The world’s attention is focused on the Covid-19 outbreak, in which SARS-CoV-2 has infected over 3 million people worldwide with high morbidity and mortality. While the pandemic is causing global health and socioeconomic disruption, nations are turning to their scientists for help. Now, many scientific institutions are committed to launching studies on this viral disease from different angles. Can the expertise of the BioIron community contribute to these efforts?
Iron biologists have long observed a link between iron and infection with a variety of microbial and viral pathogens; the links between iron and viral infection are both direct and indirect. Transferrin receptor 1 can serve as cell surface receptor for multiple viruses, iron-containing proteins are required for viral replication and packaging, and hepcidin regulation can affect patient outcomes in chronic viral infections (see (Drakesmith and Prentice, 2008) for an excellent review).
Our group has been studying the poly C-binding proteins (PCBPs) because of their capacity to bind and deliver iron to iron proteins in the cytosol. This family of proteins was initially identified for their RNA- and ssDNA-binding activity; subsequent studies have found them to be important host factors in RNA virus replication. PCBPs bind single-stranded nucleic acid and function in cellular RNA metabolism through interactions with C-rich sequences. RNA viruses, such as enterovirus 71, HCV, and poliovirus, contain C-rich regions and hijack PCBPs for their own replication. The binding of PCBPs to C-rich sequences in viral 5’ UTRs, internal ribosome entry sites (IRES) or programmed ribosomal frameshifting (PRF) sites (Li et al., 2019) are critical for viral replication.
Host iron proteins were identified in recent proteomics studies of SARS-CoV-2; among them are heme oxygenase 1, the heme transporter FLVCR, the iron-sulfur subunit B of succinate dehydrogenase SDHB, and the mitochondria-associated iron-sulfur protein CISD1 (Gordon et al., 2020). Studies of other RNA viruses have also identified components of the of viral replication machinery in association with host iron proteins, such as mitochondrial aconitase, the iron-containing, RNA helicase DDX1, and the iron chaperones PCBP1/2 (Lim et al., 2016).
Do both iron- and RNA-binding activities of PCBPs mediate their pro-viral properties? Have PCBPs evolved to simultaneously facilitate iron-protein activation and nucleic acid binding? If iron proteins involved in viral RNA processing are also dependent on PCBPs, then PCBPs may participate in several steps of viral replication through interaction with different host factors. Targeting host iron proteins important for virus replication cycle could be considered a strategy for antiviral treatment.
Gordon, D.E., Jang, G.M., Bouhaddou, M., Xu, J., Obernier, K., White, K.M., O’Meara, M.J., Rezelj, V.V., Guo, J.Z., Swaney, D.L., et al. (2020). A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature.
Li, Y., Firth, A.E., Brierley, I., Cai, Y., Napthine, S., Wang, T., Yan, X., Kuhn, J.H., and Fang, Y. (2019). Programmed -2/-1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily Conserved Mechanism. J Virol 93.
It is with great sadness that we report the passing of Dr. Philip Aisen on April 10th, 2020, at age 91. Phil was an early pioneer in studies of proteins of iron metabolism and played a pivotal role in the development of the field as we know it today. Phil along with Drs. Pauline Harrison and Ernie Huehns organized the first conference on proteins of iron transport and storage in London in 1973 from which the International Bioiron Society was eventually formed. In 2012, a special issue of BBA on Transferrins: Molecular Mechanisms of Iron Transport and Disorders (edited by Fadi Bou-Abdallah) was dedicated to Phil. The dedication, which is reproduced below, summarizes his many contributions to the bioiron field but also captures the essence of the man and his family.
Philip Aisen, M.D., has had a long and storied career studying the biochemical and physiological properties of the transferrins. Because of the large body of knowledge contributed by Phil and his laboratory over so many years, his name has become synonymous with transferrin. The history of transferrin itself began in 1945 when Swedish biochemists C. G. Holmberg and C. B. Laurall reported on a high molecular weight iron-binding component in porcine serum. They discovered this component almost by accident during studies of serum copper. Two years later they demonstrated that this pink component was a protein of molecular weight c.a. 88,000 which bound two iron atoms but also bound copper. They correctly predicted that it was a carrier of iron, naming it “transferrin” after its iron transport and transferring properties. They also demonstrated that, while copper binds to transferrin, it preferentially binds to other serum proteins and that in serum, transferrin itself is devoid of copper.
In the early 1960’s after completing his residency in internal medicine, Phil Aisen began working on the copper centers of ceruloplasmin. At the time, he was one of the early investigators in the developing field of metallobiochemistry. He published a series of papers on ceruloplasmin in the JBC and Nature. However, his research interests soon shifted to iron and, in 1966, he published his first paper on transferrin in the JBC entitled “Studies on the binding of iron to transferrin and conalbumin”. This work was soon followed by a large number of papers on the physicochemical properties of the transferrins. In those early days, Phil was the first to show that transferrin also binds chromium, cobalt and manganese in addition to iron and copper. Forty-two years and many investigations later, we now know that the protein binds virtually all transition metals and many of the lanthanides.
The obligate requirement of (bi)carbonate binding for iron binding is one of the unique aspects of transferrin chemistry. Phil undertook one of the first studies of the anion binding properties of transferrin with collaborators Roland Aasa and Tore Vänngård while on a Guggenheim fellowship during 1966-1967 in the lab of Bo Malmström. In 1967 they confirmed that (bi)carbonate binding was required for metal binding but that other suitable anions could also serve this purpose. Phil correctly predicted that the anion probably served as a linkage between the protein and metal, a prediction borne out by the crystal structure of lactoferrin published some 20 years later by Ted Baker and colleagues. It was in Gothenburg, Sweden, in Malmström’s lab that Phil also learned EPR, a spectroscopic method which he later employed with great effectiveness throughout his career to extract information about the metal binding sites of the transferrins but of other proteins as well. From the large body of early work, Phil became the acknowledged authority on transferrin.
Phil has always been a strong advocate for fundamental studies of the role of iron in biology. With Pauline Harrison and Ernie Huehns, he jointly organized the first conference on Proteins of Iron Storage and Transport which was held in London in 1973. That first meeting was devoted exclusively to transferrin and ferritin, the key players in iron metabolism known at the time. This iron meeting became a biannual event. It eventually covered all aspects of iron metabolism as new information regarding mechanisms of iron homeostasis became available and new players were discovered. Over the years this conference has grown enormously in attendance. The formation of the International BioIron Society (IBIS) many years later was an outgrowth of these meetings. The IBIS continues to grow and flourish, holding biannual meetings throughout the world, traced back to that first meeting in 1973.
During the 1970’s, much interest centered on the Fletcher-Huehns hypothesis concerning the physiological role of the two iron binding sites in the mechanism of iron transport. A key question at the time was whether the two metal binding sites of transferrin were structurally and functionally distinct. A classic JBC paper in 1978 by Leibman, Zweier and Aisen reported the four microscopic site binding constants for transferrin as measured by equilibrium dialysis and urea-gel electrophoresis to separate and quantify the four species of transferrin. This work unequivocally demonstrated that the two sites have different affinities for iron and that the occupancy of one site influenced the iron binding strength of the other despite the fact that the sites are located some 45 Å apart in separate lobes of the protein. This thermodynamic study, while a major advance itself, also laid the framework for thinking about the kinetics of iron release from transferrin. Four microscopic rate constants would also be required to describe the dynamics of this system.
The Aisen lab went on to address the kinetics of iron release from the protein by physiological chelators, ultimately studying the role of the transferrin receptor and pH in this process. This work built upon the early studies of Evan Morgan, who first showed that transferrin bound to its receptor is internalized within the cell, and the later work of the Lodish and Klausner groups deciphering many of the details of this process. The Aisen lab developed methods for obtaining the C-lobe half transferrin and initiated studies of the effects of the individual lobes on the binding of the protein to its receptor. They first demonstrated that iron is preferentially released from the C-lobe at the endosomal pH ~5.6, a finding in marked contrast to the behavior of the protein in the absence of the receptor. Thus, the receptor was shown to modulate the release of iron from transferrin as well as to serve as a carrier of the iron laden protein into the cell. This seminal work helped to lay the foundation for further work on transferrin-receptor binding and iron release kinetics subsequently carried out in other laboratories and led to many lively debates in the literature on the respective roles of the two lobes in these processes.
In the intervening years, Phil also worked in a number of other important research areas, including iron uptake from transferrin and ferritin by liver Kupffer cells. Phil and coworkers demonstrated that, in the presence of iron, ascorbate generated radical species leading to cell death, a finding of relevance to the toxicity of ascorbate in iron overload disease. He also published a series of seminal papers on uteroferrin, a purple acid phosphatase isolated from the amniotic fluid of porcine pregnancies. He demonstrated that the diiron center redox cycles between the purple ferric and pink ferrous forms and that the latter is the enzymatically active form.
Phil has published some 200 articles, spanning 55 years of research activity well past the normal age of retirement. His most recent paper was published in 2010 in the JMB. His many comprehensive reviews covering nearly all aspects of iron metabolism have been valuable resources for the research community. Additionally, Phil has served on the editorial boards of Biometals, Hepatology, Journal of Inorganic Biochemistry and Biochemical Journal and was chair of the Gordon Conferences on Metals in Biology and on Magnetic Resonance in Biology and Medicine. He chaired the Bioanalytical and Metallobiochemistry Study Section of the NIH and was a frequent ad hoc member of special study sections. Phil was an often sought-after member of review panels because of his breadth of knowledge and ability to assess the intrinsic value of proposed research. He set high standards, but was always fair in his reviews, and offered encouragement to young scientists. He was a mentor to me and to those who worked in his lab or were otherwise fortunate enough to collaborate with him and have the opportunity to learn from him.
Phil received his A.B. degree Phi Beta Kappa in Philosophy in 1949 and his M.D. degree from the Columbia College of Physicians and Surgeons. He completed internship and residencies at Mount Sinai Hospital. In 1970, after three years as Manager of Biochemical Research at the IBM Watson Laboratory at Columbia, he moved to the Albert Einstein College of Medicine. Although most of Phil’s research can be broadly classified as biophysical/bioinorganic chemistry and cellular physiology of iron, he continued to see patients throughout much of his research career. He felt that it was important to keep a hand in the clinical side of medicine. His science was better for it.
What is particularly remarkable is the fact that Phil had limited formal schooling in advanced mathematics, chemistry and physics and yet his papers rely heavily on these subjects. He is largely self-taught in these areas, possessing an in-depth knowledge of them which is clearly reflected in his papers and the graduate courses he has taught at Einstein. He has given courses in spectroscopy and quantum mechanics, biophysics and physical chemistry of macromolecules, not the usual subjects taught by an M.D.. In his retirement, Phil, ever seeking a challenge, has been teaching himself abstract algebra by working his way through Hungerford’s book, an endeavor which helps to keep the mind sharp. Three of his grandchildren are versed in advanced mathematics and occasionally lend a hand with some of the more arcane proofs of abstract algebra as Phil grapples with Galois theory, quarternions, cyclic groups, matrices of spin Hamiltonians and more than 100 theorems to date.
On a personal note, Phil met May at a summer camp in 1946. She was a drama counselor and he was a nature counselor. They started dating a year later and were married in August 1951. May and Phil had two sons Alex and Paul, both physicians and researchers, and a daughter Judith, an attorney. They have nine grandchildren, Benjamin, Amanda, Daniel, Joshua, Adam, Ariel, Noah, Andrew and Samuel. Son Alex is Professor of Radiology at Indiana University and Paul is a Professor in the Department of Neurosciences at the University of California – San Diego. One comes away from a visit to the Aisen home with a strong sense of family. The Aisens were frequently warm and generous hosts for many a traveling scientist who stayed at their home while visiting New York. Sadly, May passed away quite unexpectedly on February 1st, 2011. She was well known and beloved among the iron community, frequently accompanying Phil on his travels. May was a spunky lady with great wit and intellect and much fun to be with. She is missed by all who knew her.
While Phil at the age of 82 no longer has an active research laboratory, he retains a passionate interest in the biochemistry of iron, science in general and medicine. When you are with Phil you can always count on a lively conversation. That is still true to this day. His many contributions have helped to lay the foundation for much of the iron biochemistry currently being carried out in laboratories throughout the world. The transferrincommunity of scholars and indeed the field of iron metabolism owes a great deal to Philip Aisen. To him we dedicate this volume.
N. Dennis Chasteen
Professor of Biophysical Chemistry, Emeritus
University of New Hampshire
Durham, NH 03861
*Reproduced with permission from (2012) “Transferrins: Molecular Mechanisms of Iron Transport and Disorders”, F. Bou-Abdallah (ed), BBA General Subjects, 1820, Issue 3, pp 159-160.
Maria de Sousa (1939-2020), Professor Emeritus of the University of Porto, passed away on 14th April, a victim of COVID-19. She was notable as an immunologist, a writer, a patron of sciences and arts and for intense civic intervention.
If one could put a label on her life and legacy, it should be as a scientist always “ahead of her time” with a rare “courage to question”. At the age of 25, she left her country, family and friends to start a research life at Delphine Parrott’s lab in London. This act alone, an almost unheard-of decision in those times in Portugal, indicated already her bravery and independence. Based on good training at the microscope, she rapidly made the original observation that thymus derived cells (T-cells) had the capacity to migrate and arrange themselves in specific areas of the peripheral lymphoid organs, a phenomenon she subsequently (as Lecturer at the University of Glasgow) called ‘ecotaxis’. That discovery marked her first entry in the immunology textbooks and is still cited (Parrott and de Sousa, Nature 1966). Subsequent studies of the maldistribution of lymphoid cells between the blood and affected organs in Hodgkin’s disease children, then with Charlotte Tan at the Sloan Kettering Institute for Cancer Research in New York, led her to postulate in 1978 that “the lympho-myeloid system and its circulating components participate in the recognition and binding of metals as a protective device against metal toxicity and the preferential use of indispensable metals such as Fe or Zn by bacteria or transformed cells”. This idea marked her decision to return to Portugal in 1985 to the Abel Salazar Institute for Biomedical Sciences (ICBAS) of the University of Porto, to study hemochromatosis (before the HFE gene was identified) as a model to explore the relationship between iron and the immune system. This took her to the seminal description of an experimental model of spontaneous iron overload in the ß2microglobulin knock out mice (de Sousa et al, Immunology Letters 1994). With the identification of the HFE as an MHC class I like gene, her insistence on the existence of a critical but complex interaction between iron metabolism, blood cells and the immunological system was vindicated. More recently in her typically provocative way, she named this concept as “hemmunology”. Today, iron and the immune system is a topic never missing in the BioIron and EIC meetings.
Maria’s legacy goes far beyond her scientific discoveries. After returning to Portugal, she completely changed the science scenario in the country. At ICBAS she created and directed the first Masters course in Portugal, at a time when the Bologna Process was not even a project. In teaching she was highly innovative and pioneering. On her own words: “teaching science is the best way to learn and advance”, so it is necessary to develop a “university without walls”, because “that is where the good questions and the intelligent forms of looking for answers are”. With that spirit she coordinated in 1996 the fusion of 3 Masters courses to create the Graduate Program on Basic and Applied Biology (GABBA), a program internationally recognized for its excellence, and which attracted not only a whole generation of brilliant students, today in top positions in science worldwide, but also teachers and researchers from all over the world and from different areas of science, including Iron Biology.
As a mentor, she was tough, combative, and demanding. As a scientist she was creative, visionary and extremely rigorous. As a friend, she was sweet, wise, understanding, and incredibly good company. Maria de Sousa was unique and compelling, and leaves an inspiration and a legacy that will last for many years to come.
Maria de Sousa, a world renowned outstanding scientist, internationally recognised for her scientific discoveries in the area of the immunology and iron metabolism, has died a victim of Covid-19.
Maria de Sousa was born in Lisbon in 1939. After graduating in medicine in 1963, from the Faculty of Medicine of Lisbon, she began her scientific research career. England, Scotland, United States and Portugal – this was the scientific geography of her life.
Between 1964 and 1966, she was at the Experimental Biology Laboratories at Mill Hill, London, with a grant from the Calouste Gulbenkian Foundation. It was in London that she made a great discovery that can be found today in any immunology manual, related to lymphocytes Area T and already at the University of Glasgow, the concept of ecotaxis, a name she gave to the migration of lymphocytes.
She then obtained a doctorate in immunology in 1972, remaining in Scotland until 1975. From there she went to the United States – to the Sloan Kettering Institute for Cancer Research (in New York), Cornell Medical School (in New York) and Harvard Medical School (in Cambridge, Boston).
In 1984, she returned to Portugal to contribute to the development of scientific research in the country. In 1985, she became a full professor of immunology at the Abel Salazar Institute of Biomedical Sciences (ICBAS), in Porto.
Later, she contributed to the implementation of external and independent evaluation of Portuguese research centers, which did not exist in Portugal until the mid-1990s, when she was invited by the then Minister of Science and Technology, José Mariano Gago, to coordinate this process, in the area of health sciences.
Owner of a very exigent and critical spirit, she emphasized the need to acknowledge the insatisfaction with what is presently known and how we know it.
Her generosity to younger generations was endless as she cared deeply for the future of scientific research in Portugal and worldwide. She was dedicated to improving funding for research projects, scientific positions, opportunities for young scientists, in order to pursue the answers for all the questions left open in science.
She was fascinated with the lives and journey of lymphocytes, and she was deeply curious about the role of lymphocytes in defending against iron toxicity.
Having the privilege of calling this incredibly bright mind a friend, I shared in her worries about protecting patients with chronic kidney disease (such as herself) from excessive IV iron administration, a battle still underway.
As she said in her last class entitled “A school without walls”, on 16 October 2009, at the age of 70: “At the end of an academic life, the gifts that any plant would naturally like to leave, are her seeds and the possibility of finding new soils for the new roots (…)”.
When she knew that she had contracted Covid-19, she left a poem to her friends.
The e-mail subject was “far from being ready”.
“Love letter in a virus pandemic
Bagpipes played in Scotland
Tenors sing from verandas in Italy
The dead will not hear them
And the living want to mourn their dead in silence
Who do they want to cheer?
But the children are also dying
In my circumstance
I may die
Wondering if I will ever see you again
But before I die
I want you to know
How much I care for you
How much I worry about you
How much I remember shared and cherished moments
The feather that the gull took to our table
Golden cuff links
Socks pijamas and other thoughtful things
All moment then
As I may die and you must live
In your living the hope of my lasting”
May her spirit rest in peace and smile upon our love for her, an inspiration for everyone who knew her.
In our living, her lasting.
Last year, the Board of Directors of the BioIron Society amended the Bylaws and changed the name of our society from IBIS-the International BioIron Society to BioIron: the International Society for the Study of Iron in Biology and Medicine. Our previous logo contains the old name IBIS. The Board of Directors decided that we would like to involve our society members and announce a competition for a new logo.
Your ideas are welcome! Please submit your logo suggestions by May 1, 2020 to firstname.lastname@example.org
Both computer-generated and hand-drawn submissions are acceptable. Please send your logo suggestions as a PNG file.