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.