Category Archives: In Memoriam

In Memoriam of Philip Aisen

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.

Dedication*

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
USA

*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.

In Memory of Maria de Sousa

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?
The children?
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
Moments then
Eternities now
Poetry
Laughter  
The sea 
sunsets
The feather that the gull took to  our table 
Breakfast
Golden cuff links
The magnolia
The hospital
Socks pijamas and other thoughtful things
All moment then
Eternities now
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.
Patricia Carrilho

In Memory of Marianne Wessling-Resnick

Marianne Wessling-Resnick passed away on November 13th, 2019 after a long and private struggle with breast cancer. She was 61 years old. Marianne was a Professor of Nutritional Biochemistry in the Department of Genetics & Complex Diseases at the Harvard School of Healthin Boston, Massachusetts. A native of the Boston area, Marianne obtained her BS degree in Chemistry from Worcester Polytechnic Institute and a PhD in Biomedical Sciences from UMass Medical School. In 1990, she started as Assistant Professor in the Department of Nutrition at the Harvard School of Public Health, where she moved through the ranks to Professor in 2000. In addition to her research and teaching, Marianne served as a standing member and chair of three consecutive NIH study sections (1998–2012), chair of East Coast Iron Club (1994–1996), co-chair of the FASEB Conference on Micronutrients: Trace Elements (2001), and director of the PhD Program in Biomedical Sciences at the Harvard Graduate School of Arts and Sciences (2010–2014). Marianne’s research over the years covered wide territory including biochemical, molecular, and cellular mechanisms of iron transport and homeostasis, manganese transport and neurotoxicity, and endocytic vesicle trafficking. In recent years, she was known throughout the nutritional biochemistry community for her many contributions to our understanding of how iron status and genetic factors regulate iron and manganese uptake via intestinal, pulmonary, and olfactory pathways. Having trained over 30 post-doctoral fellows in her laboratory at Harvard, she was highly regarded as a dedicated and supportive mentor of the next generation of biomedical scientists. As such, she was frequently sought—by junior faculty at Harvard and beyond—for her solid advice on career and life. She seemed to know something about everything, was generous with her time and advice, and despite a strong exterior, she was known by many as a remarkably caring and compassionate individual. She will be dearly missed by hercolleagues and friends at Harvard, the BioIron Society, and the trace element community. Marianneis survived by her husband Paul Resnick and her son Timothy.

Mitch Knutson (University of Florida), Khristy Thompson (Harvard School of Public Health), Jonghan Kim (Northeastern University), and Young-Ah Seo (University of Michigan)

Prem Ponka Legacy

Prem Ponka (born as Přemysl Poňka) passed away while at a conference in Paris. He was Professor of Physiology at McGill University and Senior Investigator at the Lady Davis Institute for Medical Research in Montreal, Canada. He obtained his MD in 1964 and his PhD (in Physiology) in 1969 from Charles University, Prague. From 1968 to 1979 he served as an Assistant Professor in the Department of Pathophysiology at Charles University in Prague. As Czechoslovakia was then under an oppressive communist rule, he emigrated to Montreal in 1979 under difficult circumstances, and resumed his academic career at McGill and the Lady Davis Institute. While still behind the “iron curtain”, Prem developed an interest in the study of iron and heme metabolism and throughout his career continued making major contributions in this area of research. Prem demonstrated that iron uptake is the limiting factor for erythroid heme synthesis. He formulated the ‘kiss-and-run hypothesis”, according to which iron is directly delivered from endosomes to mitochondria in erythroid cells. He discovered a critical role of the heme catabolic enzyme heme oxygenase in erythroid cell physiology. Furthermore, Prem developed a new class of cell permeable iron chelators (SIH, PIH and analogues), which are widely used by researchers in the field. Prem was an active member of the BioIron Society and organized its first international conference in Prague in 2005. He also organized an earlier “iron conference” in Montebello, Quebec, in 1987. Prem was an acclaimed scientist who received broad recognition for his work, and was in high demand as a lecturer and peer-reviewer of manuscripts and grant proposals in Canada, USA, Czech Republic and elsewhere. He was a devoted colleague with encyclopedic knowledge of the history and personalities of the bioiron field, and a renaissance man with a broad interest in science, history, philosophy and arts. He was a dedicated proponent of political and intellectual freedom and tolerance, with a unique sense of humor. Prem had no plans to retire and passed away as an active scientist, exactly as he envisioned. He is survived by his wife Dr. Jitka Ponka, adult children Dr. David Ponka and Claire Ponka, and grandchildren. Prem will be greatly missed by his colleagues at the BioIron Society, McGill University and the Lady Davis Institute.

Kostas Pantopoulos (McGill University) and Tomas Ganz (UCLA)

In memory of Leo Richard Zacharski

It was with great sadness that we learned that Leo Richard Zacharski, MD, passed away on August 23, 2019 at the age of 81. 

Leo Richard Zacharski 

Leo attended Wayne State University and then received his MD degree in 1962 from Wayne State Medical School in Detroit. He served an internship at Harper Hospital in Detroit followed by a residency in internal medicine and subspecialty training in hematology at the Mayo Clinic in Rochester, Minnesota. He served as a Captain in the US Army Medical Corp from 1966 to 1968. He was appointed Assistant Professor of Medicine at Dartmouth Medical School and Staff Physician at the VA Hospital in White River Junction, Vermont in January 1970. He specialized in diagnosis and treatment of patients with bleeding and clotting disease, and also iron overload disease. While early motivations were toward medical missions, the heart of his career was devotion to biomedical research believing that he could best serve humanity through discovery and innovation. He was awarded Research Career Development positions at the VA hospital and became the Associate Chief of Staff for Research there in 1985, a position held until retirement from the VA in 2004. During his tenure with the VA he authored over 250 published papers and over 100 abstracts. He served as Chairman of three National VA Cooperative Studies. He achieved the rank of Professor of Medicine in 1985 and became Professor of Medicine Active Emeritus in 2013. Devotion to his “calling” prompted continuation of his research following retirement. His most productive years followed retirement during which he coined the term, “ferrotoxic disease”, referring to diseases of aging caused by oxidative stress due to progressive iron accumulation. He was a member of the American College of Physicians, American Society of Hematology, International Society on Thrombosis and Haemostasis, International BioIron Society and East-West Iron Club; and served on the Medical Advisory Board of the Iron Disorders Institute (irondisorders.org). His personal Christian faith prompted deep appreciation of the elegant intricacy and beauty of the “natural order” which was the basis for his devotion to biomedical research.

Xi Huang, Ph.D.

Founder and President

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