The occurrence in nature of proteins with hemagglutinating activity that in later years were shown to be sugar-specific and eventually named lectins has been known since the turn of the 19th century, but until about two decades ago they aroused little interest (for a historical survey, see Ref. 1Sharon N. Lis H. Lectins: from hemagglutinins to biological recognition molecules. A historical overview.Glycobiology. 2004; 14: 53R-62RCrossref PubMed Scopus (0) Google Scholar). My own involvement with these proteins began inadvertently and initially on a part-time basis in the early 1960s after my return to the Weizmann Institute from two and a half years of exciting and educational postdoctoral studies in the United States. During the first of these I worked in the laboratory of Fritz Lipmann at the Massachusetts General Hospital, Boston. Lipmann, one of the most influential biochemists of the last century, was then interested in the mechanism of protein biosynthesis. I was assigned to study the amino acid activation reaction (the first step in this process), work that resulted in two publications (2Sharon N. Lipmann F. Reactivity of analogs with pancreatic tryptophan-activating enzyme.Arch. Biochem. Biophys. 1957; 69: 219-227Crossref PubMed Google Scholar, 3Hoagland M.B. Zamecnik P.C. Sharon N. Lipmann F. Stulberg M.P. Boyer P.D. Oxygen transfer to AMP in the enzymatic synthesis of the hydroxamate of tryptophan.Biochim. Biophys. Acta. 1957; 26: 215-217Crossref PubMed Google Scholar). Concurrently, I greatly enriched my knowledge of biochemistry, mainly from my fellow postdoctoral students, and especially from the guest seminars in which ongoing biochemical discoveries and developments were reported. I spent the second postdoctoral year at the Massachusetts General Hospital with Roger Jeanloz, a leading carbohydrate chemist, where I got my training in the subject and also succeeded in isolating an unusual diamino sugar from a Bacillus polysaccharide I had brought with me from Rehovot (4Sharon N. Jeanloz R.W. The diaminohexose component of a polysaccharide isolated from Bacillus subtilis.J. Biol. Chem. 1960; 235: 1-5Abstract Full Text PDF PubMed Google Scholar) (see below); the remaining time I worked with Dan Koshland at Brookhaven National Laboratory on the mechanism of action of myosin ATPase (5Levy H.M. Sharon N. Koshland Jr., D.E. Purified muscle proteins and the walking rate of ants.Proc. Natl. Acad. Sci. U. S. A. 1959; 45: 785-791Crossref PubMed Google Scholar, 6Levy H.M. Sharon N. Lindemann E. Koshland Jr., D.E. Properties of the active site in myosin hydrolysis of adenosine triphosphate as indicated by the O18-exchange reaction.J. Biol. Chem. 1960; 235: 2628-2632Abstract Full Text PDF PubMed Google Scholar). Dan was then starting to make his mark on enzymology with his “induced fit” concept of enzyme action, originally greeted with much skepticism (7Koshland Jr., D.E. Crazy, but correct.Nature. 2004; 432: 447Crossref PubMed Scopus (0) Google Scholar). Back at Rehovot my original aim was to establish the structure of that diamino sugar; I was fortunate to receive for this purpose my first National Institutes of Health (NIH) grant, a modest one of some $25,000 for 3 years. (This would have been unheard of at the present time because nothing was known then about the function of the compound.) The task took me (with a couple of graduate students) over a decade; eventually we were able to prove by degradation and synthesis that the compound in question, which we named bacillosamine, is 2,4-diamino-2,4,6-trideoxy-d-glucose (8Zehavi U. Sharon N. Structural studies of 4-acetamido-2-amino-2,4,6-trideoxy-d-glucose (N-acetylbacillosamine), the N-acetyl diaminosugar of Bacillus licheniformis.J. Biol. Chem. 1973; 248: 433-438Abstract Full Text PDF PubMed Google Scholar, 9Liav A. Hildhesheim J. Zehavi U. Sharon N. Synthesis of 2-acetamido-2,6-dideoxy-d-glucose (N-acetyl-d-quinovosamine), 2-acetamido-2,6-dideoxy-d-galactose (N-acetyl-d-fucosamine) and 2,4-acetamido-2,4,6-trideoxy-d-glucose from 2-acetamido-2-deoxy-d-glucose.Carbohydr. Res. 1974; 33: 217-227Crossref Scopus (36) Google Scholar). To my delight, the di-N-acetyl derivative of bacillosamine has recently been found attached glycosidically to the amide of asparagine or the hydroxyl of serine in the carbohydrate-peptide linkage region of several interesting glycoproteins of pathogenic bacteria (10Weerapana E. Imperiali B. Asn-linked protein glycosylation: from eukaryotic to prokaryotic systems.Glycobiology. 2006; 16: 91R-101RCrossref PubMed Scopus (0) Google Scholar). By a strange twist of fate, most of these glycoproteins were originally isolated in 2002 by Martin Young and his colleagues at the National Research Laboratories, Ottawa, from Campylobacter jejuni by affinity chromatography on immobilized soybean agglutinin (SBA) (11Young N.M. Brisson J.R. Kelly J. Watson D.C. et al.Structure of the N-linked glycan present on multiple glycoproteins in the Gram-negative bacterium, Campylobacter jejuni.J. Biol. Chem. 2002; 277: 45230-45239Abstract Full Text Full Text PDF Scopus (321) Google Scholar), the first lectin I got involved with 40 years earlier. My studies of SBA began together with Halina Lis with whom it has been my good fortune to collaborate to this very day. It aroused our curiosity not because of its ability to bind sugars specifically and reversibly and to agglutinate cells, the hallmarks of proteins of this class, but because of other reasons that I shall presently mention. We did not have the slightest idea that lectins would become extremely useful carbohydrate-specific reagents, that they would be found to function as mediators of cell recognition, or that they would make a major contribution to glycobiology (12Taylor M.E. Drickamer K. Introduction to Glycobology.2nd Ed. Oxford University Press, Oxford, UK2006Google Scholar). In fact, for a time we were not even aware of the term lectin, which was originally proposed in 1956 by William C. Boyd from Boston University for blood type-specific hemagglutinins. Because SBA, like the majority of the hemagglutinins, is not blood group-specific, we began referring to it as a lectin only in 1970, when it occurred to us that the original definition should be broadened to include all cell-agglutinating and sugar-specific proteins (13Sharon N. Lis H. Lectins: cell agglutinating and sugar-specific proteins.Science. 1972; 177: 949-959Crossref PubMed Google Scholar). Our interest in SBA developed in the course of investigations on soybean proteins carried out within the framework of a generous and long term grant from the United States Department of Agriculture that I received in 1961 jointly with Katchalski-Katzir (14Katchalski-Katzir E. My contributions to science and society.J. Biol. Chem. 2005; 280: 16529-16541Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Katchalski was the founding Head of the Department of Biophysics at the fledgling Weizmann Institute, which was officially inaugurated in 1949. I came to the department in 1954 after having received my Ph.D. degree from the Hebrew University, Jerusalem; Halina, with a Ph.D. degree from Uppsala University, joined the department 5 years later. The purpose of the above grant was to carry out a fundamental study of the soy proteins with the aim of providing information for their improved utilization for human nutrition. Katchalski and I were persuaded to embark on this project by Tim (M. L.) Anson and Aaron Altschul, close friends, noted protein chemists, and enthusiastic believers in these proteins as the best solution to world hunger. After some time, Katchalski became immersed in his pioneering studies of polyamino acids as protein models and on enzyme immobilization and turned over the whole project to me, for which I am extremely grateful. Halina and I set out by trying to obtain pure proteins from soybeans by chromatographic techniques, but this proved to be a difficult task as most of them lack biological activity, are poorly soluble, and undergo complex association-dissociation reactions. We therefore chose to focus on SBA, originally isolated and characterized in the 1950s by Irvin E. Liener at the University of Minnesota, St. Paul. The main reason for our choice was the evidence presented by Liener that it contained glucosamine, raising the likelihood that it may be a glycoprotein (15Wada S. Pallansch M.J. Liener I.E. Chemical composition and end groups of soybean hemagglutinin.J. Biol. Chem. 1958; 233: 395-400Abstract Full Text PDF PubMed Google Scholar). In those days, research on glycoproteins was in its infancy, but I became intrigued by these compounds because of my interest in carbohydrates, as described elsewhere (16Sharon N. Half a century between carbohydrates and proteins. Comprehensive Biochemistry.in: A History of Biochemistry. Vol. 41. Elsevier Publishing Co., Amsterdam2000: 391-448Google Scholar). Working on SBA, Halina and I soon found that it contains not only glucosamine but also mannose. We then isolated from a proteolytic digest of SBA an asparaginyloligosaccharide that contained all the N-acetylglucosamine and mannose of the lectin (17Lis H. Sharon N. Katchalski E. Soybean hemagglutinin, a plant glycoprotein. I. Isolation of a glycopeptide.J. Biol. Chem. 1966; 241: 684-689Abstract Full Text PDF PubMed Google Scholar). Eventually we also isolated from the lectin N-acetylglucosaminylasparagine (18Lis H. Sharon N. Katchalski E. Identification of the carbohydrate-peptide linking group in soybean agglutinin.Biochim. Biophys. Acta. 1969; 192: 364-366Crossref PubMed Google Scholar), the carbohydrate-peptide linking group, that was identical with the one originally obtained in 1963 by Albert Neuberger, the founding father of modern glycoprotein research, in his pioneering studies of ovalbumin. As pointed out recently by Liener (19Liener I.E. A trail of research revisited.J. Agric. Food Chem. 2002; 50: 6580-6582Crossref PubMed Scopus (3) Google Scholar), “The fact that SBA was shown to be a glycoprotein may not be particularly surprising to the modern day biochemists, but at the time the finding of a sugar moiety in a plant protein was accepted with reservation. It was thought that glycoproteins were strictly of animal origin and that the finding of a sugar with a plant protein was most likely because of noncovalent contamination.” In 1981, jointly with Hans (J. F. G.) Vliegenthart from the University of Utrecht, the complete structure of the carbohydrate of SBA was established by NMR as the branched oligomannoside Man9(GlcNAc)2, found in animal glycoproteins too, demonstrating that protein N-glycosylation is a process conserved in plants and animals (20Dorland L. van Halbeek H. Vliegenthart J.F.G. Lis H. Sharon N. Primary structure of the carbohydrate chain of soybean hemagglutinin. A reinvestigation by high resolution 1H NMR spectroscopy.J. Biol. Chem. 1981; 256: 7708-7711Abstract Full Text PDF PubMed Google Scholar). A unique feature of SBA is that all its molecules carry the same oligosaccharide (21Ashford D.A. Dwek R.A. Rademacher T.W. Lis H. Sharon N. The glycosylation of glycoprotein lectins. Intra- and inter-genus variation in N-linked oligosaccharide expression.Carbohydr. Res. 1991; 213: 215-227Crossref PubMed Scopus (0) Google Scholar) in contrast to essentially all other glycoproteins, which bear a variety of glycans at each attachment site, i.e. consist of mixtures of distinct glycoforms. SBA serves therefore as an excellent source of this oligosaccharide (for an example, see Ref. 22Deras I.L. Kawasaki N. Lee Y.C. Quantitative recovery of Man9GlcNAc2Asn from concanavalin A.Carbohydr. Res. 1998; 306: 469-471Crossref PubMed Scopus (0) Google Scholar). Our few 1960s publications on SBA attracted little attention, and we sometimes felt like wanderers in a desert. Although the studies of lectins were in their eighth decade and several hundreds of these proteins (almost all from plants) had already been identified, the handful of other scientists active in the field at the time did not fare better. Irwin J. Goldstein from the University of Michigan at Ann Arbor, still a leading lectin researcher, tells that when he sent a note in 1963 to Biochemical and Biophysical Research Communications describing the purification of concanavalin A by affinity chromatography, it was rejected forthright because “this represents a modest advance in an obscure area.” The note was eventually published in the Biochemical Journal (23Agrawal B.B.L. Goldstein I.J. Specific binding of concanavalin A to cross-linked dextrans.Biochem. J. 1965; 96: 23c-25cCrossref Scopus (0) Google Scholar), and affinity chromatography soon became the method of choice for lectin isolation. However, as the 1960s were folding, the attitude toward lectins began to change, and a number of leading biochemists and immunologists, among them Gerald Edelman at Rockefeller University, Mel Greaves at London University, Elvin Kabat at Columbia University, Jerker Porath at Uppsala, and Jon Singer at University of California, San Diego, became involved with them. The reasons for this change in attitude were summarized by Kabat, who had become intrigued with lectins primarily because their combining sites seemed similar to those of antibodies and who in 1977 stated: “During the past 10 years there has been an extraordinary burst of activity in the study of plant and animal lectins, stimulated largely by the findings that they have specific receptor sites for carbohydrates and react with glycoproteins in solution or on cell membranes...” (24Kabat E.A. Dimensions and specificities of recognition sites on lectins and antibodies.J. Supramol. Struct. 1978; 8: 79-88Crossref PubMed Google Scholar). In 1970, affinity chromatography of glycoproteins on immobilized lectins was introduced (among others) by Donnely and Goldstein (25Donnely E.H. Goldstein I.J. Glutaraldehyde-insolubilized concanavalin A: an adsorbent for the specific isolation of polysaccharides and glycoproteins.Biochem. J. 1970; 118: 697-698Google Scholar). It became a must at one step or another for the isolation of membrane proteins, all of which are glycosylated, a classical case being that of the insulin receptor with the aid of wheat germ agglutinin (WGA) (26Jacobs S. Schechter Y. Bissell K. Cuatrecasas P. Purification and properties of insulin receptors from rat liver membranes.Biochem. Biophys. Res. Commun. 1977; 77: 981-988Crossref PubMed Google Scholar). Lectins proved also to be useful for the separation of purified glycoproteins into their glycoforms, i.e. differently glycosylated forms of the same protein. A very recent telling example is of different glycoforms of IgG with different degrees of sialylation, obtained by fractionation on the sialic acid-specific Sambucus nigra agglutinin and shown to differ in their anti-inflammatory activity (27Kaneko Y. Nimmerjahn F. Ravetch J.V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation.Science. 2006; 313: 670-674Crossref PubMed Scopus (1201) Google Scholar). Interest in lectins intensified with the realization that they are extremely valuable reagents for the investigation of cell surface sugars, for the assessment of the role of the latter in cell growth and differentiation, in interactions of cells with their environment, and also in a variety of pathological processes. In this connection it is instructive to refer to two classical studies with lectins that provided very early evidence for the presence of sugars on cell surfaces and their potential role as cell identity markers, a common theme in modern glycobiology. One came from the laboratory of James Sumner at Cornell University, Ithaca, who in 1919 isolated concanavalin A in crystalline form but only in 1936, together with Howell, reported that it agglutinates cells such as erythrocytes and yeasts and that this agglutination is inhibited by sucrose, thus demonstrating for the first time the sugar specificity of lectins (28Sumner J.B. Howell S.F. Identification of concanavalin A with the hemagglutinin of jack bean.J. Bacteriol. 1936; 32: 227-237Crossref PubMed Google Scholar). Moreover, with much foresight they suggested that the hemagglutination induced by the lectin might be a consequence of its reaction with carbohydrates on the surface of the red cells. The other study was by Walter Morgan and Winifred Watkins at the Lister Institute, London, who in the early 1950s used blood type-specific hemagglutinins to show that the blood type A immunodeterminant is α-linked N-acetylgalactosamine and that the H(O) determinant is α-l-fucose (reviewed in Ref. 29Morgan W.T.J. Watkins W.M. Unraveling the biochemical basis of blood group ABO and Lewis antigenic specificity.Glycoconjugate J. 2000; 17: 501-530Crossref PubMed Scopus (0) Google Scholar). This was the first demonstration that cell surface carbohydrates can serve as carriers of biological information. Much excitement was created in the following decade by the reports of Joseph C. Aub from the Massachusetts General Hospital (30Aub J.C. Sanford B.H. Wang L.H. Reactions of normal and leukemic cell surfaces to a wheat germ agglutinin.Proc. Natl. Acad. Sci. U. S. A. 1965; 54: 400-402Crossref PubMed Google Scholar) and Max Burger from Princeton University (31Burger M. Goldberg A.R. Identification of a tumor-specific determinant of neoplastic cell surfaces.Proc. Natl. Acad. Sci. U. S. A. 1967; 57: 359-366Crossref PubMed Google Scholar), who were both working with WGA (specific for N-acetylglucosamine and N-acetylneuraminic acid), and of Leo Sachs with Michael Inbar from the Department of Genetics of our Institute, who used concanavalin A (specific for mannose and glucose) (32Inbar M. Sachs L. Interaction of the carbohydrate-binding protein concanavalin A with normal and transformed cells.Proc. Natl. Acad. Sci. U. S. A. 1969; 63: 1418-1425Crossref PubMed Google Scholar), that these lectins agglutinated malignantly transformed cells but not their normal parental cells. The reports provided compelling evidence that cancer might be associated with a change in cell surface sugars, an idea that only a few years before had been considered completely unfounded. In collaboration with Leo Sachs and Ben-Ami Sela, we found soon thereafter that SBA (specific for galactose and N-acetylgalactosamine) also possesses the remarkable ability to distinguish between normal and malignant cells (33Sela B.A. Lis H. Sharon N. Sachs L. Different locations of carbohydrate-containing sites at the surface membrane of normal and transformed mammalian cells.J. Membr. Biol. 1970; 3: 267-279Crossref PubMed Scopus (0) Google Scholar). Numerous subsequent studies have demonstrated that high susceptibility to agglutination by lectins is a property shared by many, albeit not all, malignant cells. Several basic features of membranes were revealed, or their existence confirmed, with the aid of lectins. Thus, using ferritin-conjugated concanavalin A and ricin as an electron microscopic probe, Garth Nicolson and Jon Singer at University of California, San Diego, found that the lectin derivatives bind specifically to the outer surface of the human and rabbit erythrocyte membrane and concluded that the oligosaccharides of the plasma membrane of eukaryotic cells are asymmetrically distributed (34Nicolson G.L. Singer S.J. Ferritin-conjugated plant agglutinins as specific saccharide stains for electron microscopy: application to saccharides bound to cell membranes.Proc. Natl. Acad. Sci. U. S. A. 1971; 68: 942-945Crossref PubMed Google Scholar). Further support for such distribution was obtained by Vincent Marchesi at Yale University, who used ferritin-labeled phytohemagglutinin (PHA) and showed that glycophorin, the major sialoglycoprotein of the human erythrocyte membrane, is oriented so that its carbohydrate-carrying segment is exposed to the external medium, whereas the other segments of the same molecule are embedded in the lipid bilayer or protrude into the cytoplasm (35Marchesi V.T. Tillack T.W. Jackson R.L. Segrest J.P. Scott R.E. Chemical characterization and surface orientation of the major glycoprotein of the human erythrocyte membrane.Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 1445-1449Crossref PubMed Google Scholar). Other ultrastructural studies with lectins provided some of the most convincing evidence for the fluid mosaic membrane model of Singer and Nicolson, according to which the membrane consists of proteins and glycoproteins floating in a lipid bilayer (reviewed in Ref. 36Nicolson G.L. Interactions of lectins with animal cell surfaces.Int. Rev. Cytol. 1974; 39: 89-190Crossref PubMed Google Scholar). Prominent among these was the finding of the lectin-induced clustering and patching of the corresponding membrane receptors on lymphocytes and other kinds of cell, as illustrated for example by the treatment with fluorescein-labeled concanavalin A of rat or mouse lymphocytes (37Inbar M. Sachs L. Mobility of carbohydrate-containing sites on the surface membranes in relation to control of cell growth.FEBS Lett. 1973; 32: 124-128Crossref PubMed Scopus (0) Google Scholar). Reorganization of cell surface carbohydrates was later shown to be required for various activities of lectins on cells such as mitogenic stimulation and induction of apoptosis. The toxicity for animals of certain plant lectins has been recognized since the earliest days of lectin research, at the end of the 19th century. However, research on the toxic action of lectins on cells started only many decades later with special attention being paid to mammalian cell lines (e.g. CHO and BHK) resistant to different lectins, primarily the highly toxic ricin and the less toxic PHA and WGA (reviewed in Ref. 38Stanley P. Glycosylation mutants and the functions of mammalian carbohydrates.Trends Genet. 1987; 3: 77-81Abstract Full Text PDF Google Scholar). Leading the field was one cell phenotype independently isolated in 1974 by Stuart Kornfeld at Washington University, Colin Hughes at the National Institute for Medical Research, Mill Hill, London, and Pamela Stanley at Toronto University, Canada. This phenotype lacked GlcNAc transferase I, the key enzyme in the biosynthesis of complex and hybrid N-linked carbohydrate units of glycoproteins. Soon thereafter many other lectin-resistant cell lines with different enzymatic glycosylation defects became available. They proved extremely valuable for the investigation of the biosynthesis of glycoproteins and glycolipids and of the function of their carbohydrates, especially those expressed on the cell surface. Currently they also serve for the large-scale production of pharmacologically useful glycoproteins such as erythropoietin. In the fall of 1970 I arrived at the Department of Biochemistry, University of California at Berkeley, for a sabbatical year as Visiting Professor. My host was Clint Ballou with whom I discussed at length the possibility of using lectins to examine the ideas on the roles of carbohydrates as information and recognition molecules. Such ideas had been entertained by Saul Roseman from Johns Hopkins University (39Roseman S. The synthesis of complex carbohydrates by multiglycosyltransferase systems and their potential function in intercellular adhesion.Chem. Phys. Lipids. 1970; 5: 270-297Crossref PubMed Scopus (784) Google Scholar) and Victor Ginsburg at the NIH (40Ginsburg V. Kobata A. Rothfield L.I. Structure and Function of Surface Components of Mammalian Cells in Structure and Function of Biological Membranes. Academic Press, New York1971: 439-459Google Scholar). Although there existed a few books and several reviews on lectins, none of them dealt with their molecular properties nor did they indicate their enormous potential as tools for biological research. Because Dan Koshland from the same department at Berkeley was then a member of the editorial board of Science, I approached him with the suggestion that I write a review on lectins for that journal. This suggestion was readily accepted by Philip Abelson, then editor of Science. Writing was started by me in the fall of that year in the laboratory of Albert Neuberger at St. Mary's Hospital in London, where I arrived for a few months to study lysozymes, on which Neuberger and I were at that time working. However, I ended up purifying WGA by ion exchange chromatography from commercial wheat germ together with Tony (A. K.) Allen, separating it into three isolectins and showing that its specificity is similar to that of lysozyme (41Allen A. Neuberger A. Sharon N. The purification and specificity of wheat germ agglutinin.Biochem. J. 1973; 131: 155-162Crossref PubMed Google Scholar), because it too exhibited a pronounced affinity not only for oligosaccharides derived from chitin, as originally demonstrated by Burger and Goldberg (31Burger M. Goldberg A.R. Identification of a tumor-specific determinant of neoplastic cell surfaces.Proc. Natl. Acad. Sci. U. S. A. 1967; 57: 359-366Crossref PubMed Google Scholar), but also of peptidoglycan. In addition we also proved that, contrary to suggestions in the literature, WGA was not a glycoprotein. This work further stimulated the interest of Neuberger in lectins with which he continued to be engaged for several years into his eighties. The Science review was completed jointly with Halina upon my return to Rehovot early in 1972 (13Sharon N. Lis H. Lectins: cell agglutinating and sugar-specific proteins.Science. 1972; 177: 949-959Crossref PubMed Google Scholar). It summarized the history of the research on lectins since their discovery, their specificity for monosaccharides and cells, and the properties of concanavalin A and the few other lectins that had been purified at the time. The changes that occur on cell surfaces upon malignant transformation, as revealed by lectins, were discussed, although their significance was not clear and doubts were raised by us, amply supported later, as to whether they are a distinctive characteristic of malignant cells. Regardless of this, we concluded that lectins, both native and modified, provide a new and useful tool for the study of the chemical architecture of cell surfaces. Finally, we dealt in brief with the speculations on the role of lectins in nature, about which nothing was known with certainty. Another review on lectins was published by us in the following year in the Annual Review of Biochemistry (42Sharon N. Lis H. The biochemistry of plant lectins (phytohemagglutinins).Annu. Rev. Biochem. 1973; 42: 541-574Crossref PubMed Scopus (758) Google Scholar) and a third appeared in the same series in 1986 (43Lis H. Sharon N. Lectins as molecules and tools.Annu. Rev. Biochem. 1986; 55: 35-67Crossref PubMed Google Scholar). In these reviews we tried to convey to the readers our fascination and enthusiasm for the subject. In 1989 we prepared a monograph on lectins and in 2003 a second edition of the same (44Sharon N. Lis H. Lectins. Chapman & Hall, London1989Crossref Google ScholarLectin's.2nd Ed. Kluwer Academic Publishers, Dordrecht, The Netherlands2003Google Scholar), both of which have been translated into Japanese. Some 20 years ago I coedited a treatise on lectins to which Halina and I contributed several chapters (45Liener I.E. Sharon N. Goldstein I.J. The Lectins, Properties, Functions and Applications in Biology and Medicine. Academic Press, Orlando, FL1986Google Scholar). A related activity of mine was the publication in 1975 of a book entitled “Complex Carbohydrates” in which lectins are featured and where I expressed my firm belief “that the specificity of many natural polymers is written in terms of sugar residues, not of amino acids or nucleotides” (46Sharon N. Complex Carbohydrates, Their Properties, Biosynthesis and Functions. Addison Wesley, Reading, MA1975Google Scholar). The book was based on notes that I prepared for the graduate students taking my course on the same subject and remained in use for a long time. I still continue teaching this course, now under the title “Molecular and Cellular Glycobiology.” The 1970s witnessed the intensification of the study of the molecular properties of individual lectins, a prerequisite for a deep understanding of their activities at the molecular level. In 1972 concanavalin A became the first of these proteins for which the primary and three-dimensional structures have been established, the latter by x-ray crystallography. This was thanks to the efforts of Gerald Edelman's group at the Rockefeller University (47Edelman G.M. Cunningham B.A. Reeke Jr., G.N. Becker J.W. Waxdal M.J. Wang J.L. The covalent and three-dimensional structure of concanavalin A.Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 2580-2584Crossref PubMed Google Scholar) and of the efforts of Karl Hardman and Clinton F. Ainsworth at Argonne National Laboratories (48Hardman K.D. Ainsworth C.F. Structure of concanavalin A at 2.4 Å resolution.Biochemistry. 1972; 11: 4910-4919Crossref PubMed Google Scholar). The fold first observed in this structure, an elaborate arrangement of extended beta strands into two sheets, became known as the jelly roll or lectin fold (126Srinivasan N. Rufino S.D. Pepys M.B. Wood S.P. Blundell T.L. A superfamily of proteins with the lectin fold.Chemtracts Biochem. Mol. Biol. 1986; 6: 149-164Google Scholar). The publication of the concanavalin A structure was soon followed by the determination by Christine Schubert Wright at Virginia Commonwealth University of the three-dimensional structure of WGA as well as of its complexes with ligands even before the complete amino acid sequence of this lectin had become available (49Wright C.S. The crystal structure of wheat germ agglutinin at 2.2 Å resolution.J. Mol. Biol. 1977; 111: 439-457Crossref PubMed Scopus (0) Google Scholar). It is worth noting that at present the structures of close to