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Biographical Memoirs: Volume 56 (1987)

Chapter: William H. Stein

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Suggested Citation:"William H. Stein." National Academy of Sciences. 1987. Biographical Memoirs: Volume 56. Washington, DC: The National Academies Press. doi: 10.17226/897.
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WILLIAM H . STEIN June 25, 1 91 1-February 2, 1 980 BY STANFORD MOORE W~ ~ ~ ~ A M H . S T E ~ N began his autobiographical sketch for the 1972 volume of Nobel lectures as follows: I was born June 25, 1911, in New York City, the second of three children, to Fred M. and Beatrice Borg Stein. My father was a businessman who was greatly interested in communal affairs, particularly those dealing with health, and he retired quite early in life in order to devote his full time to such matters as the New York Tuberculosis and Health Association, Mon- tefiore Hospital, and others. My mother, too, was greatly interested in communal affairs and devoted most of her life to bettering the lot of th children of New York City. During my childhood, I received much en- couragement from both of my parents to enter into medicine or a fun- damental science. His early education was at the LincoIn School of the Teachers College of Columbia University. It was a so-callecI "progressive school" of the time; in addition to fostering in- terest in the creative arts, music, writing, and sports, the cur- riculum includecI well-taught courses in chemistry, physics, and biology, with field trips that he enjoyed. From those years, he used to recall that his first scientific project as a student was as an avicI collector of moths and butterflies. At sixteen, he transferred to a preparatory school in New En- gland, Phillips Exeter Academy, which offered a clemanding educational experience that he felt strengthened his work habits and his precision of writing. 415

416 BIOGRAPHICAL MEMOIRS In 1929 he matriculated at Harvard, as had his father and his older brother before him. He majored in chemistry; the scientific background thus achieved led him to spend one year as a grac;luate student at Harvard in chemistry. It was suggested to him, however, that he might enjoy the devel- oping subject of biochemistry more than organic chemistry per se. As a result, in 1934 he transferred to the Department of Biological Chemistry at the College of Physicians and Sur- geons, Columbia University. He found the environment most challenging. Hans Clarke, the chairman, hacI succeeded in gathering a stimulating faculty and a group of unusually giftec! graduate students from around the world. Nearly a dozen of those students became outstandingly productive biochemists. During his graduate-student clays, in 1936, William Stein married Phoebe Hockstader. His wife and their three sons William H., fir.; David F.: and Robert T. were to be invalu- able resources for a creative scientist throughout a career in which science and family were intimately interwoven. Stein lived on Manhattan most of his life, with an interlude in Scarsdale, New York, while the children were of school age. He enjoyoc! summer retreats both at Cos Cob, with oppor- tunities for tennis and swimming, and, in the later years, at WoocIbury, in Connecticut. William Stein completecT his Ph.D. thesis in 1937, uncter the guidance of E. G. Miller, Jr.; the subject was the amino acid composition of elastin. Thus began a lifelong concern with the chemistry of proteins. His first experiment was the preparation of elastin from the ligamentum nuchae of the ox. In the course of applying some of the gravimetric meth- o(ls of the time, he used two precipitants that had been (le- velopect by Max Bergmann potassium trioxalatochromiate for glycine and ammonium rhodanilate for proline. He was introcluced to these methods by Erwin Brand at Columbia, who tract worked with Bergmann in Germany.

WILLIAM H. STEIN 417 Bergmann had arrived in the Unitec! States from Dresden in 1934 to become a member of The Rockefeller Institute for Meclical Research in New York. When Stein completer! his studies for the Ph.D. clegree at Columbia in 1937, it was a logical progression for him to move southward] on Manhattan to join the Bergmann group. Again, Stein found himself in an exceptionally stimulating environment; Bergmann was at- tracting a talentect international group of postdoctoral assist- ants, many of whom became prominent biochemists. Among the current Academy members from this group are Joseph S. Fruton, Emil L. Smith, Klaus Hofmann, ant! Paul Za . mecnik. There were two main lines of investigation in the Berg- mann laboratory: the specificity of proteolytic enzymes and the structural chemistry of proteins. Stein initially applied his talents to the task of trying to improve gravimetric methods for amino acid determination. His first contribution to meth- octology was his introduction of the concept of the solubility product method in an attempt to permit quantitative results to be obtained with reagents that gave sparingly soluble salts of amino acids. Stanford Moore joined the Bergmann labo- ratory in 1939, arriving via Vanclerbilt ant! Wisconsin. Berg- mann suggested that Stein anc! Moore pool their efforts to see whether the solubility product method could be clevel- opec! into a practical analytical procedure. Through careful attention to the details of gravimetric analysis, using two of the reagents introduce by Bergmann, they were able to determine glycine with 5-nitronaphthalene- i-sulfonic acid as the precipitating agent and leucine with 2-bromo- toluene-5-sulfonic acid. The method was applied to hyctro- lysates of egg albumin and silk fibroin. But the future was to provide methods that were to be less tedious anct more micro. At this stage, the research on amino acid! analysis was in- terrupted by the war years. The laboratory was engaged

418 BIOGRAPHICAL MEMOIRS under contract to the Office of Scientific Research and De- velopment to look for possible therapeutic agents for vesicant war gases through stu(ly of the physiological mechanisms of action of mustard gas and the nitrogen mustards. Stein was a coauthor of a series of fundamental papers concerned with the chemistry of the reactions of mustard gas and related compounds with the functional groups of amino acids and peptides. During the war years, in 1944, illness took the life of Max Bergmann at the age of fifty-eight. The members of the lab- oratory carried the war work to completion in 1945, at which time most of them moved on to other positions. For three years, Moore hac! been out of the laboratory ~ (A . ,~ serving the Office of Scientific Research and Development in administrative capacities in Washington ant! on other war- time assignments. Stein and Moore debatecT whether to ac- cept appointments elsewhere or to ask the Director of The Rockefeller Institute, Herbert S. Gasser, whether he would give them a chance to see what they could accomplish on the Rockefeller scene. Gasser offered the two young investigators an opportunity, on a trial basis, to initiate a research program that might merit continuccI support. With that challenge, they starte(1 with the premise, born of the Bergmann years, that accurate establishment of the amino acid compositions of proteins is a first step toward progress in determination of their chemical structures. In 1945 it was possible to take a completely new look at the problem of amino acid analysis. The renaissance in chro- matography stimulate(1 by A. J. P. Martin anti R. L. M. Synge in England, together with Lyman C. Craig's development of liquid-liquic! countercurrent distribution in his laboratory just clown the corridor from the Bergmann department at Rockefeller, brought to the attention of biochemists the potential resolving power of multi-plate separations. After

WILLIAM H. STEIN 419 weighing the possibilities for speed, resolution, simplicity, and quantitativeness, Stein and Moore cleciclect to try column chromatography. Thus began several busy years of close col- laborative effort on the clevelopment of methods ant! equip ment. . After initial experiments in which the fractions were col- lectect by hand, a photoelectric cirop-counting fraction col- lector was built to expedite the collection of the effluent in a series of small fractions of precise volume; it was the proto- type for the commercially built fraction collectors based upon this principle that became wiclely user! in biochemistry. Then a simple and sensitive quantitative method for measuring the concentration of amino acid in each tube was needed. The ninhyctrin reaction hac! been introcluced by Ruhemann in 1911~. The blue-colored product is sensitive to oxidation; in initial trials the results did not obey Beer's law. When the reaction was carried out anaerobically, the yielct was im- provec! and linearity was approached, but such a procedure was inconvenient. An oxygen-free environment in solution in an open tube was attained by including a dissolved reduc- ing agent, such as stannous chloride or the recluced form of ninhydrin (hydrinciantin). A water-miscible organic solvent (first, methyl Cellosolve, and later, dimethy! sulfoxide) was aciclec! to keep the blue-colored reaction product (diketohy- drindyliclene-diketohydrinciamine) and hydrinciantin in so- lution. This method of measurement was first used to mon- itor the peaks elutecT from columns of potato starch operated with n-butanol-water as the solvent system, a type of chro- matogram first tried by Synge. With a neutral solvent, the use of a preliminary wash with S-hyciroxyquinoline was found essential to prevent metals in the starch from distorting the separations. Over a period of several years, quantitative sys- tems with starch columns were clevelopecl for determining all of the common amino acids of protein hydrolysates and were .

420 BIOGRAPHICAL MEMOIRS appliect to the analysis of ,E\-lactogIobulin and bovine serum albumin in 1949. The results were welcome, but it took two weeks to run the three starch columns required. Faster analyses became possible when finely powdered ion exchange resins became available for chromatography. With 1 fin . 1 1 . sul~onatea polystyrene resins, several years ot exploratory chromatograms lee! to the use of buyers of different pHs at different temperatures for the serial elusion of all of the com- mon amino acids of proteins and of physiological fluicts. In the early 1950s, the time for each analysis was reclucect to about five clays. With an efficient chromatographic method at hand, the next stage was to render the process automatic. This project in instrumentation was undertaken in cooperation with Dar- re! Spackman and lecl to an automatic amino acid analyzer in 1958. The eluent was pumped through the resin bed at several atmospheres of pressure. The ninhycirin color was cleveloped in the flowing stream and the optical density was recordecl potentiometrically; a hy(lrolysate was analyzecl in an overnight run. Subsequent academically ant! commer- cially introduced improvements have utilizer! finer resins and higher pressures and have attained sixty-minute analyses. The resulting amino acid analyzers found a worIc~wicle mar- ket and represented the first wiclely used form of high- performance liquid chromatography. In the writing of the papers on methoclology every effort was made to include all of the details needled for elective use of the methods. This enterprise was facilitatect by circulating preprints to biochemists who expresses! an immediate inter- est in using the procedures and who could check the com- pleteness of the experimental directions in advance of pub . . Cation. During the early years of our cooperation, Stein anct I worked out a system of collaboration that lasted for a lifetime.

WILLIAM H. STEIN 42 Stein combined an inventive mine! and a creep dedication to science with great generosity. Over a period of forty years, we approached problems with somewhat different perspec- tives and then focused our thoughts on the common aim. If ~ die! not think of something, he was likely to, and vice versa, and this process of frequent interchange of ideas accelerated progress in research. It also helped in the writing of papers. never ciraftect a text that Stein could not improve. The methodology was developed with the primary aim in mind of opening new approaches to the study of the chemical structures of proteins. After the first four years of the above studies, Gasser decided that the two young investigators were making enough progress to merit being hosts to a postctoc- toral fellow. In 1949, they attracted Werner Hirs from Co- lumbia University. A key decision at that time was the choice of the protein to study. In Englancl, Frederick Sanger hac! his classic studies on insulin well uncler way, for which he was able to use qualitative methods in large part. The study of longer polypeptide chains wouIc! gain from quantitative anal- yses at each step. And an enzyme would be an appealing subject for stucly because the structural knowledge couict provide a baseline for determination of specific residues in- volved in the enzyme-substrate interactions. Bovine pan- creatic ribonuclease, a protein about twice the size of insulin, was readily available ant] had been partially purified at Rockefeller by Dubos and Thompson and by Kunitz. Hirs extended the technique of ion exchange chromatography to ribonuclease on a polymethacrylic acid resin. In 1952 Gasser clecided that Stein and Moore qualifier! as members of The Rockefeller Institute for Medical Research; the title became professor when the institution assumed its role in graduate education as The Rockefeller University under the administration of DetIev Bronk. The research on chromatographically purified RNase A

422 BIOGRAPHICAL MEMOIRS was then extended, with Hirs, to the development of meth- ods for the ion exchange chromatography of peptides ob- tained by tryptic and chymotryptic hydrolysis of the chain in which the four disulfide bonds had been split by oxiclation. I. Leggett Bailey joined the oroiect to stud the nentides lib 1 J J 1 1 eratec' oy pepsin. Thus began the collection of data from which a sequence for the enzyme could be deduced, with the invaluable additional aid of the sequential degradation re- action newly introduced by Pehr Eciman in Sweden in 1950. At the time that these studies on ribonuclease were begun, Christian B. Anfinsen and his associates at NIH also turned to ribonuclease as an appropriate molecule for structural study; the combined results from the two laboratories (ex- periments in progress were freely discussed) expedited the solution of the problem. The determination of the final se- quence, to which Darre} Spackman and Derek Smyth were contributors at Rockefeller, also dependec1 upon a key obser- vation at NTH by Erhard Gross and Bernhard Witkop, ob- tained through the application of their ingenious method of cleavage at methionine residues by cyanogen bromide. Thus, for the first time, the chemical formula of an enzyme could be written. Derivatization experiments were then undertaken at Rockefeller in order to identify residues at or near the active site. Todoacetate was the first reagent studied. The enzyme was known to be inactivated by the reagent; at that time rapid reaction with iodoacetate was thought of primarily as an in- dication of-SH groups. When it was established that ribo- nucicase did not have any-SH groups, an evident task was to ascertain what was happening. Through experiments be- gun by Gerd GundIach' amino acid analysis was used to show that, depending upon pH, the reagent could alkylate pri- marily methionine, histidine, or lysine residues in the en- zyme. Arthur Crestfield showed that in thirty minutes at pH 5.5, the principal reaction was with the imidazole group of

WILLIAM H. STEIN 423 one of two specific histicline residues, yielding a carboxy- methy] group either on the I-nitrogen of histidine- ~ 19 or on the 3-nitrogen of histidine-12. Through Robert Heinrikson's ciata on the effect of carboxymethylation of the e-NH2 group of {ysine-41 on these reactions, it was possible to conclucle that in the three-ctimensional structure of the enzyme the reactive nitrogens of histidine- 12 ant! histicline- ~ ~ 9 were about 5 Angstroms apart at the active site of the catalyst and that the s-NH2 group of lysine-41 was 7-10 Angstroms from nitrogen-3 of histidine-12. These three-dimensional predic- tions, macle on chemical grounds, were borne out by the sub- sequent x-ray crystallographic analyses of Frederic Richards and HaroIct Wyckoff at Yale. One of the questions posed to George Stark was whether these two uniquely reactive histidine residues would still be especially reactive toward iodoacetate if the molecule were unfolded in ~ M urea. As expected, they are not. But in one of these experiments he detected, by amino-acic! analysis, a sicle reaction that turned out to be carbamylation of lysine residues by traces of cyanate in the urea to give homocitrul- line. This observation served as one of several reminders that, as demonstrated in ~ X28 by WohIer, ammonium cyanate and urea are in equilibrium. One of those thus remincled was Anthony Cerami, then a student in another laboratory at Rockefeller. Some years later, when he heard that urea was being administerec! to patients with sickle cell anemia, he wondered whether cyanate merited consideration as the pos- sible active agent in such an experiment. He elicitec! the co- operation of lames Manning, who had recently joined the Stein and Moore laboratory. From the investigations of the two young men, there grew a decade of research on the ef- fectiveness of the carbamylation of hemoglobin S in convert- ing the molecule to one of almost normal physiological func- tion. From RNase A, with 124 amino acid residues, attention

424 BIOGRAPHICAL MEMOIRS was turned to bovine pancreatic deoxyribonuclease; chro- matography on phosphocellulose yiel(lect a homogeneous preparation of DNase A, which proved to be a glycoprotein with a single pepticle chain of 257 residues. The sequence of DNase A was establishect in 1973 as a result of several years of researches by Paul Price (as a graduate stuclent), Teh-yung Liu, Brian Catley, Johann SaInikow, ant! Ta-hsiu Liao. Acldi- tional experiments were conclucted by Tony Hugli, Bryce Plapp, and Dalton Wang. The result was a thorough knowI- edge of the chemistry of the enzyme, its existence in four chromatographically distinct forms (A, B. C, and D), and identification of special features of each isozyme. Stein, throughout his life, in his generous manner, took a special interest in facilitating the careers of scholars whose sojourns in the laboratory made possible the exploration of many facets of the researches. A number of enzymes were the subjects of studies of specific aspects of protein structure and function. For seventeen years, Stein was the principal investigator on a grant from the National Institute of General Medical Sciences, NIH, to study that subject. Some of the enzymes, in actdition to RNase and DNase, that the labora- tory stu(liecl with partial support from that grant were: bro- melains (with Shoshi Ota), chymotrypsin (with Denis C. Shaw), pepsin (with T. G. Rajagopalan, T. A. A. Dopheide, and Roger Lundblad), streptococcal proteinase (with Teh- yung Liu, William FerctinancI, Brenda Gerwin, Norbert Neu- mann, Michael C. Lin, anti Michael Bustin, in cooperation with the enzyme's discoverer, Stuart D. Elliott), ribonuclease To (with Kenji Takahashi), 2',3'-cyclic nucleotide 3'-phos- phohyctrolase from brain (with Arabinda Guha, David C. So- gin, and Robert I. Drummond), and carboxypepticiase Y (with Rikimaru Hayashi). Stein took a particular interest in the application of the chromatographic methods to the analysis of physiological

WILLIAM H. STEIN 425 fluids for amino acids. One of his earliest uses of the proce dure was in a quantitative study of the major ninhy(lrin-pos- itive constituents of human urine. He extendecT his studies to cystinuria, and the laboratory, in collaboration with Alexan- der Bearn of The Rockefeller Hospital, investigates! the ami- noacicluria of Wilson's disease. Part of that stucly required adaptation of the method to the measurement of blood plasma amino acids as well. In cooperation with Harris Tal- lan, the free amino acids of mammalian tissues were also surveyed in cletail. Out of these several studies grew the identification of 3-methy~histictine and tyrosine-O-sulfate as normal constituents of human urine, anc! the observations that acetylaspartic acid is a major metabolite in brain and that cystathionine is a principal amino acid in human brain. In a study with Alejan(lro C. Paladini, phenylacety~glutamine was found to be a normal major metabolic product in human urine. One of the first applications of the amino acid analysis procedure was to human hemoglobin A prepares! electro- phoretically by Henry Kunke} of The Rockefeller Hospital; the absence of isoleucine was clemonstratec! to be one crite- rion for the purity of this protein. That stucly led to a reex- amination (with R. David Cole) of the cysteine content of human hemoglobin. Stein combined his~research efforts at Rockefeller with service in a number of capacities on the national and inter- national scenes. He was a visiting professor at the University of Chicago in 1961, ant! at Harvard University in 1964. His lectures there, throughout his travels, and to graduate stu- clents at Rockefeller conveyed an exciting picture of the ho- rizons that new methods were opening in the stucly of the chemical structure of proteins. He was a member of the Med- ical Advisory Boarc! of Hebrew University-Hadassah Meclical School, Israel, 1957-70; trustee of Montefiore Hospital in

426 BIOGRAPHICAL MEMOIRS New York, i 947-74; and member of the Council of the In- stitute of Neurological Diseases and Blindness of NIH,1961- 66. He was vice-chairman of the U.S. National Committee for the International Union of Biochemistry, 1962-63, chair- man, 1965-6S, and chairman of the Publications Committee for the Sixth International Congress of Biochemistry held in New York in 1964. He anti his wife enjoyed the worIc~wicle travel that was an integral part of his career and the oppor- tunity to host the scholars from many countries who came through New York City in the course of their journeys. His major pastimes were directly related to the life of a scientist with international interests. The American Society of Biological Chemists drew upon his editorial skill, beginning in 1955, when he was elected to the Eclitorial Committee. He was chairman of the Committee from 1958 to 1961. He was an active participant in the search that lect to the appointment of John Eclsall to the editorship of The journal of Biological Chemistry in 195S, upon the retire- ment of Rudolph I. Anderson. Stein joined the Editorial Board of the journal in 1962. In his drafts of editorial letters he was quick to praise a fine manuscript, to decline an inacl- equate one, and careful to explain in gracious cletai! the op- tions for revision when that seemed necessary. Two years later he was asked by Ecisall to assume one of the three associate editorships. As Edsall's ten-year term as editor drew toward a close, Stein was asked by the Council of the Society to consider the position. He accepted and took a leading part in setting up the administrative procedures that wouIcl facilitate the han- dling of the increasing numbers of manuscripts that were being received as the journal grew in size. The changes in- cludect the organization of a permanent central office at the Society's headquarters in Bethesda to which all manuscripts wouIcT go initially. Stein hacI earlier hac! a key role in the

WILLIAM H. STEIN 427 recruitment of Robert A. Harte as full-time executive secre- tary of the Society; Harte was macle business manager of the Journal and Edith Wolff was the first executive assistant. A staff was thus establishecI to hancIle the innumerable business details associated with receiving more than 3,000 manu- scripts annually and managing the publication of editorially acceptable texts. Stein's foresight in centralizing the first step in the edito- rial process, with the view of facilitating the transfer of the editorship to the next recipient, was tested-tragically- much too soon. He was stricken by major illness in 1969, after a year and a half in the position. In 1969, while in attendance at an international sympo- sium on proteolytic enzymes being held in Copenhagen, Stein clevelopec! a high fever that preventer! him from giving the paper he was scheclulec! to present. A few clays later, en route home by air, paralysis began. He barely survived the acute phase of the disease, which was cliagnosect as a severe case of GuilIain-Barre syndrome. After a year of hospitali- zation, he remained a quadriplegic. He met this tragedy with great courage and with preservation of his sense of humor. His wife anc! their three sons helped him immeasurably to meet the almost unbelievable frustrations of a disabled per- son possessing the intellectual cirive of a creative brain that was fully functional to the last clay. The Rockefeller Univer- sity, uncler the administrations of Frederick Seitz and Joshua Lederberg, was host to Stein's determinecT endeavors during eleven years of this difficult existence. He, of course, hac! to relinquish the editorship of the fournal in 1969, but he con- tinued to provide welcome advice, both on specific manu- scripts and on matters of policy, to Herbert Tabor, his suc cessor. Stein hac! the pleasure of seeing the subject of RNase grow in interest rather than taper off. When the laboratory's work

428 BIOGRAPHICAL MEMOIRS on the enzyme was begun, the protein was viewer as a catalyst of rather limited physiological interest; it was recognized as one of the enzymes of the digestive tract. Work from several laboratories on the presence of RNases of the pancreatic type in most mammalian cells ant! of a widely clistributed specific inhibitor of the enzyme broadened the scope of the subject. Stein followed with enthusiasm the researches of the young associates in the laboratory on the isolation of the inhibitor in pure form from human placenta anc! the establishment of its molecular properties. He made the uncomfortable jour- ney by wheelchair to his office at Rockefeller whenever he felt able, ant! he was a valuable consultant to all of the mem- bers of the laboratory. On occasion, they wouic! meet at his home for informal seminars on current research. He took an active interest in reacting manuscripts and his editorial skill was always helpful. With the stimulating cooperation of Phoebe Stein, their home continued to be the scene of vis its by scientists from arounc! the worIct who enjoyed; the op- portunity to discuss both biochemistry and the issues of the times, which he continued to analyze with keen percep- tion. A life of sixty-eight years filled with unusual measures of accomplishment, acclaim, anti suffering came to a close on February 2, 1980, when William Stein diecI suddenly from heart failure at his home in New York. Among the many honors that Stein received were election to the National Academy of Sciences in 1960 and to the American Academy of Arts and Sciences in the same year. Awards that he shared with Moore were the American Chem- ical Society Award in Chromatography and Electrophoresis (1964), the Richards Mecial of the American Chemical Soci ety (1972), the Kaj Linderstr0m-Lang Award, Copenhagen (1972), and the Nobel Prize in Chemistry (1972), shared also

WILLIAM H. STEIN 429 with Christian B. Anfinsen. Academic honors included D.Sc. honoris cause from Columbia University (1973), D.Sc. honoris cause from the Albert Einstein College of Medicine of Yeshiva University ~ ~ 973), and the Award of Excellence Meclal from the Columbia University Graduate Faculty and Alumni Association ~ ~ 973~.

430 BIOGRAPHICAL MEMOIRS B I B L I OGRAP H Y 1938 With Edgar G. Miller. The composition of elastin. }. Biol. Chem., 125:599-614. With Carl Niemann and Max Bergmann. The quantitative deter- mination of amino acids. i. Am. Chem. Soc., 60:1703. 1939 With Max Bergmann. A new principle for the determination of amino acids, and its application to collagen and gelatin. }. Biol. Chem.,128:217-32. With Max Bergmann. Naphthalene-13-sulfonic acid as a reagent for amino acids. }. Biol. Chem., 129:609-18. 1940 With Max Bergmann. Determination of proline in mixtures con- taining 1- and dl-proline. The praline content of gelatin. I. Biol. Chem., 134:627-33. With David G. Doherty and Max Bergmann. Aromatic sulfonic acids as reagents for amino acids. I. Biol. Chem., 135:487-96. 1941 With Stanford Moore and Max Bergmann. The isolation of l-serine from silk fibroin. I. Biol. Chem., 139:481-82. 1942 With Stanford Moore, Guido Stamm, Chi-Yuan Chou, and Max Bergmann. Aromatic sulfonic acids as reagents for amino acids. The preparation of l-serine, I-phenylalanine, and l-leucine from protein hydrolysates. J. Biol. Chem., 143:121-29. With Stanford Moore and Max Bergmann. The specific rotation of l-tyrosine. }. Am. Chem. Soc., 64:724. Some current problems and recent advances in the chemistry of the proteins. Fifth Annul Meet. Am. Soc. Brew. Chem. Proc., May 22-27. 14 pp. With Stanford Moore and Max Bergmann. Protein constituent analysis by the solubility method. Chem. Rev., 30:423-32.

WILLIAM H. STEIN 1943 431 With Stanford Moore. Determination of amino acids by the solu- bility product method. i. Biol. Chem., 150: 113 -30. 1944 With Stanford Moore and Max Bergmann. Aromatic sulfonic acids as reagents for peptides. Partial hydrolysis of silk fibroid. }. Biol. Chem., 154:191-201. 1946 Amino acid analysis of proteins. Introduction. Ann. N.Y. Acad. Sci. 47, Art. 2:59-62. With Stanford Moore. The use of specific precipitants in the amino acid analysis of proteins. Ann. N.Y. Acad. Sci. XLVII, Art. 2:95-118. With Joseph S. Fruton and Max Bergmann. Chemical reactions of the nitrogen mustard gases. V. The reactions of the nitro- gen mustard gases with protein constituents. i. Org. Chem., 11 :559-70. With Joseph S. Fruton, Mark A. Stahmann, and Calvin Golumbic. Chemical reactions of the nitrogen mustard gases. VI. The re- actions of the nitrogen mustard gases with chemical compounds of biological interest. I. Org. Chem., 11 :571-80. With Stanford Moore and Max Bergmann. Chemical reactions of mustard gas and related compounds. I. The transformations of mustard gas in water. Formation and properties of sulfonium salts derived from mustard gas. I. Org. Chem., 11 :664-74. With Stanford Moore and Joseph S. Fruton. Chemical reactions of mustard gas and related compounds. II. The reaction of mus- tard gas with carboxyl groups and with the amino groups of amino acids and peptides. I. Org. Chem., 11 :675-80. With Stanford Moore. Chemical reactions of mustard gas and re- lated compounds. III. The reaction of mustard gas with methi- onine. i. Org. Chem., 11:681-85. With Joseph S. Fruton. Chemical reactions of mustard gas and related compounds. IV. Chemical reactions of {3-chloroethyl-D'- hydroxyethylsulfide. J. Org. Chem., 11:686-91. With Joseph S. Fruton and Max Bergmann. Chemical reactions of

432 BIOGRAPHICAL MEMOIRS mustard gas and related compounds. V. The chemical reactions of 1,2-bis (,3-chloroethyl)-sulfone, divinyl sulfone and divinyl sulfoxide. i. Org. Chem., 11:719-35. With Stephen M. Nagy, Calvin Golumbic, Joseph S. Fruton, and Max Bergmann. The penetration of vesicant vapors into hu- man skin. I. Gen. Physiol., 29:441-69. 1948 With Stanford Moore. Partition chromatography of amino acids on starch. Ann. N.Y. Acad. Sci. 49, Art. 2:265-78. With Stanford Moore. Chromatography of amino acids on starch columns. Separation of phenylalanine, leucine, isoleucine, me- thionine, tyrosine, and valine. i. Biol. Chem., 176:337-65. With Stanford Moore. Photometric ninhydrin method for use in the chromatography of amino acids. i. Biol. Chem., 176:367- 88. 1949 With Stanford Moore. Chromatography on amino acids on starch columns. Solvent mixtures for the fractionation of protein hy- drolysates. I. Biol. Chem., 178 :53-77. With Stanford Moore. Amino acid composition of 13-lactoglobulin and bovine serum albumin. i. Biol. Chem., 178:79-91. 1950 With Stanford Moore. Chromatographic determination of the amino acid composition of proteins. Cold Spring Harbor Symp. Quant. Biol., 14: 179-90. 1951 With Stanford 1951:35-41. With C. H. W. Hirs and Stanford Moore. Chromatography of pro- teins. Ribonuclease. i. Am. Chem. Soc., 73:1893. With Stanford Moore. Electrolytic desalting of amino acids. Con- version of arginine to ornithine. i. Biol. Chem., 190: 103-6. With Harris H. Tallan. Studies on lysozyme. l. Am. Chem. Soc., 73:2976. With Stanford Moore. Chromatography of amino acids on sulfo- nated polystyrene resins.~. Biol. Chem., 192:663-81. Moore. Chromatography. Sci. Am., March, .

WILLIAM H. STEIN 433 Excretion of amino acids in cystinuria. Proc. Soc. Exp. Biol. Med., 78:705-8. 1952 With C. H. W. Hirs and Stanford Moore. Isolation of amino acids by chromatography on ion exchange columns; use of volatile buffers. }. Biol. Chem., 195:669-83. With Stanford Moore. Chromatography. Annul Rev. Biochem., 21:521-46. 1953 With C. H. W. Hirs and Stanford Moore. A chromatographic in- vestigation of pancreatic ribonuclease. I. Biol. Chem.,200:493- 506. With Harris H. Tallan. Chromatographic studies on lysozyme. }. Biol. Chem., 200:507-14. A chromatographic investigation of the amino acid constituents of normal urine. I. Biol. Chem., 201:45-58. 1954 With Harris H. Tallan and Stanford Moore. 3-Methylhistidine, a new amino acid from human urine. i. Biol. Chem., 206:825- 34. With A. G. Bearn and Stanford Moore. The amino acid content of the blood and urine in Wilson's disease. i. Clin. Invest. 33:410- 19. With Alejandro C. Paladini, C. H. W. Hirs, and Stanford Moore. Phenylacetylglutamine as a constituent of normal human urine. I. Am. Chem. Soc., 76:2848. With C. H. W. Hirs and Stanford Moore. The chromatography of amino acids on ion exchange resins. Use of volatile acids for elusion. i. Am. Chem. Soc., 76:6063-65. With Stanford Moore. Procedures for the chromatographic deter- mination of amino acids on four percent cross-linked sulfo- nated polystyrene resins. l. Biol. Chem., 211:893-906. With Stanford Moore. A modified ninhydrin reagent for the pho- tometric determination of amino acids and related compounds. I. Biol. Chem., 211:907-13. With Stanford Moore. The free amino acids of human blood plasma. }. Biol. Chem., 211:915-26.

434 BIOGRAPHICAL MEMOIRS With Harris H. Tallan and Stanford Moore. Studies on the free amino acids and related compounds in the tissues of the cat. }. Biol. Them., 211 :927-39. With C. H. W. Hirs and Stanford Moore. The amino acid compo- sition of ribonuclease. }. Biol. Chem., 211:941-50. 1955 With Charles F. Crampton and Stanford Moore. Chromatographic fractionation of calf thymus histone. i. Biol. Chem., 215:787- 801. With Harris H. Tallan, S. Theodore Bella, and Stanford Moore. Tyrosine-O-sulfate as a constituent of normal human urine. l. Biol. Chem., 217:703 -8. 1956 With Harris H. Tallan and Stanford Moore. N-acetyl-L-aspartic acid in brain. i. Biol. Chem., 219:257-64. With C. H. W. Hirs and Stanford Moore. Peptides obtained by tryptic hydrolysis of performic acid-oxidized ribonuclease. }. Biol. Chem., 219:623-42. With }. Leggett Bailey and Stanford Moore. Peptides obtained by peptic hydrolysis of performic acid-oxidized ribonuclease. }. Biol. Chem., 221:143-50. With C. H. W. Hirs and Stanford Moore. Peptides obtained by chymotryptic hydrolysis of performic acid-oxidized ribonu- clease. A partial structural formula for the oxidized protein. }. Biol. Chem., 221: 151-69. With Stanford Moore and C. H. W. Hirs. Studies of structure of ribonuclease. Fed. Proc. Fed. Am. Soc. Exp. Biol., 15:840-48. With Stanford Moore. Column chromatography of peptides and proteins. Adv. Protein Chem., 11: 191-236. 1957 With Charles F. Crampton and Stanford Moore. Comparative stud- ies on chromatographically purified histones. }. Biol. Chem., 225:363 -86. With Henry G. Kunkel, R. David Cole, Darrel H. Spackman, and Stanford Moore. Observations on the amino acid composition of human hemoglobins. Biochim. Biophys. Acta, 24:640-42.

WILLIAM H. STEIN 435 1958 With Stanford Moore. Determination of the structure of proteins: studies on ribonuclease. Harvey Lect., 52:119-43. With Harris H. Tallan and Stanford Moore. L-cystathionine in hu- man brain. ]. Biol. Chem., 230:707-16. With Darrel H. Spackman and Stanford Moore. Automatic record- ing apparatus for use in the chromatography of amino acids. Anal. Chem., 30:1190-206. With Stanford Moore and Darrel H. Spackman. Chromatography of amino acids on sulfonated polystyrene resins. Anal. Chem., 30:1185-90. Observations of the amino acid composition of human hemoglo- bins. Conference on hemoglobin. N.A.S.N.R.C. Publ., 557: 220-26. With C. H. W. Hirs and Stanford Moore. Studies on the structure of ribonuclease. In: IUPAC Symposium on Protein Structure, ed. A. Neuberger, pp. 211-22. London: Methuen; New York: John Wiley & Sons. With Stanford Moore and Darrel H. Spackman. Automatic record- ing apparatus for use in the chromatography of amino acids. Fed. Proc. Fed. Am. Soc. Exp. Biol., 17:1107-15. With R. David Cole and Stanford Moore. On the cysteine content of human hemoglobin. }. Biol. Chem., 233: 1359-63. With Stanford Moore, R. David Cole, and Gerd Gundlach. On the cleavage of disulfide bonds in proteins by reduction. Proc. 4th Int. Congr. Biochem., 8:52-62. 1959 With H. Gerd Gundlach and Stanford Moore. The nature of the amino acid residues involved in the inactivation of ribonuclease by iodoacetate. }. Biol. Chem., 234:1754-60. With H. Gerd Gundlach and Stanford Moore. The reaction of io- doacetate with methionine. i. Biol. Chem., 234: 1761-64. 1960 With C. H. W. Hirs and Stanford Moore. The sequence of the amino acid residues in performic acid-oxidized ribonuclease. I. Biol. Chem., 235:633-47. With Darrel H. Spackman and Stanford Moore (with the assistance

436 BIOGRAPHICAL MEMOIRS of Anna M. Zamoyska). The disulfide bonds of ribonuclease. J. Biol. Chem., 235:648-59. With M. Prince Brigham and Stanford Moore. The concentrations of cysteine and cystine in human blood plasma. i. Clin. Invest., 39: 1633-38. With George R. Stark and Stanford Moore. Reactions of the cya- nate present in aqueous urea with amino acids and proteins. J. Biol. Chem., 235:3177-81. Chemical modifications of ribonuclease. Brookhaven Symp. Biol., 13: 104-14. 1961 With Stanford Moore. The chemical structure of proteins. Sci. Am., 204:81-92. With George R. Stark and Stanford Moore. Relationship between the conformation of ribonuclease and its reactivity toward io- doacetate. l. Biol. Chem., 236:436-42. 1962 With Norbert P. Neumann and Stanford Moore. Modification of the methionine residues of ribonuclease. Biochemistry, 1:68- 75. With Derek G. Smyth and Stanford Moore. On the sequence of residues 11 to 18 in bovine pancreatic ribonuclease. I. Biol. Chem., 237:1845-50. With Arthur M. Crestfield and Stanford Moore. On the aggrega- tion of bovine pancreatic ribonuclease. Arch. Biochem. Bio- phys., Suppl. 1 :217-22. 1963 With Derek G. Smyth and Stanford Moore. The sequence of amino acid residues of bovine pancreatic ribonuclease: revisions and confirmations. i. Biol. Chem., 238:227-34. With Arthur M. Crestfield and Stanford Moore. The preparation and enzymatic hydrolysis of reduced and S-carboxymethylated proteins. I. Biol. Chem., 238:622-27. With Teh-Yung Liu, Norbert P. Neumann, Stuart I). Elliott, and Stanford Moore. Chemical properties of streptococcal protein- ase and its zymogen. I. Biol. Chem., 238:251-56.

WILLIAM H. STEIN 437 With Glyn Jones and Stanford Moore. Properties of chromato- graphically purified trypsin inhibitors from lima beans. Bio- chemistry, 2:66-71. With Arthur M. Crestfield and Stanford Moore. On the prepara- tion of bovine pancreatic ribonuclease A. l. Biol. Chem., 238:618-21. With Stanford Moore. Relationship between structure and activity of ribonuclease. Proc. 5th Int. Congr. Biochem., 4:33-38. With Arthur M. Crestfield and Stanford Moore. Alkylation and identification of the histidine residues at the active site of ribo- nuclease. }. Biol. Chem., 238:2413-20. With Arthur M. Crestfield and Stanford Moore. Properties and conformation of the histidine residues at the active site of ri- bonuclease. }. Biol. Chem., 238:2421-28. With Stanford Moore. Chromatographic determination of amino acids by the use of automatic recording equipment. In: Methods in Enzymology, ed. S. Colowick and H. Kaplan, vol. 6, pp. 819- 31. New York: Academic Press. 1964 With Shoshi Ota and Stanford Moore. Preparation and chemical properties of purified stem and fruit bromelains. Biochemistry, 3: 180-85. With Denis C. Shaw and Stanford Moore. Inactivation of chymo- trypsin by cyanate. i. Biol. Chem., 239:671-73. Structure-activity relationships in ribonuclease: the active site. 6th Int. Congr. Biochem. Abstr., 32:243-44. Structure-activity relationships in ribonuclease. Fed. Proc. Fed. Am. Soc. Exp. Biol., 23:599-608. With George R. Stark. Alkylation of the methionine residues of ribonuclease in 8 M urea. i. Biol. Chem., 239:3755-61. 1965 With Teh-Yung Liu, Stanford Moore, and Stuart D. Elliott. The sequence of amino acid residues around the sulfhydryl group at the active site of streptococcal proteinase. ]. Biol. Chem., 240:1143-49. With William Ferdinand and Stanford Moore. An unusual disul- fide bond in streptococcal proteinase. l. Biol. Chem.,240:1150- 55.

438 BIOGRAPHICAL MEMOIRS With William Ferdinand and Stanford Moore. Susceptibility of re- duced, alkylated trypsin inhibitors from lima beans to tryptic action. Biochim. Biophys. Acta, 96:524-47. With Robert L. Heinrikson, Arthur M. Crestfield, and Stanford Moore. The reactivities of the histidine residues at the active site of ribonuclease toward halo acids of different structures. i. Biol. Chem., 240:2921-34. The structure and the activity of ribonuclease. Isr. I. Med. Sci. 1: 1229-43. 1966 With Brenda I. Gerwin and Stanford Moore. On the specificity of streptococcal proteinase. l. Biol. Chem., 241:3331 - 39. With T. G. Rajogopalan and S. Moore. The inactivation of pepsin by diazoacetylnorleucine methyl ester. J. Biol. Chem., 241 :4295-97. With T. G. Rajagopalan and S. Moore. Pepsin from pepsinogen. Preparation and properties. i. Biol. Chem., 241:4940-50. 1967 With T. A. A. Dopheide and S. Moore. The carboxyl-terminal se- quence of porcine pepsin. J Biol. Chem., 242: 1833-37. With S. Moore and T.-Y. Liu. Structural studies of the proteinase from group A streptococci. 7th Int. Congr. of Biochem. Abstr., 11-12. With T. A. A. Dopheide and S. Moore. Studies on the structure and activity of pepsin. 7th Int. Congr. of Biochem. Abstr., 777. With Kenji Takahashi and Stanford Moore. The identification of a glutamic acid residue as part of the active site of ribonuclease T. T Biol. Chem., 242:4682-90. 1968 With Michael C. Lin and Stanford Moore. Further studies on the alkylation of the histidine residues at the active site of pan- creatic ribonuclease. }. Biol. Chem., 243:6167-70. With B. }. Catley and Stanford Moore. The carbohydrate moiety of bovine pancreatic deoxyribonuclease. l. Biol. Chem., 244:933-36.

WILLIAM H. STEIN 1969 439 With Roger L. Lundblad. On the reaction of diazoacetyl com- pounds with pepsin. I. Biol. Chem., 244: 154-60. With Paul A. Price, Teh-Yung Liu, and Stanford Moore. Properties of chromatographically purified bovine pancreatic deoxyribo- nuclease. I. Biol. Chem., 244:917-23. With Paul A. Price and Stanford Moore. Alkylation of a histidine residue at the active site of bovine pancreatic deoxyribonu- clease. I. Biol. Chem., 244:924-28. With Paul A. Price and Stanford Moore. Effect of divalent cations on the reduction and reformation of the disulfide bonds of deoxyribonuclease. i. Biol. Chem., 244:929-32. 1970 With Michael Bustin, Michael C. Lin, and Stanford Moore. Activity of the reduced zymogen of streptococcal proteinase. }. Biol. Chem., 245:846 -69. Chemical studies on purified pepsin. In: International Symposium on Structure-Function Relationships of Proteolytic Enzymes, ed. P. Des- nuelle, H. Neurath, and M. Ottesen, pp. 253-60. New York: Academic Press. With Johann Salnikow and Stanford Moore. Comparison of the multiple forms of bovine pancreatic deoxyribonuclease. I. Biol. Chem., 245:5685-90. 1971 With Bryce V. Plapp and Stanford Moore. Activity of bovine pan- creatic deoxyribonuclease A with modified amino groups. }. Biol. Chem., 246:939-45. With Tony E. Hugli. Involvement of a tyrosine residue in the ac- tivity of bovine pancreatic deoxyribonuclease A. i. Biol. Chem., 246:7191-200. 1973 With Johann Salnikow, Ta-Hsiu Liao, and Stanford Moore. Bovine pancreatic deoxyribonuclease A. Isolation, composition, and amino acid sequences of the tryptic and chymotryptic peptides. I. Biol. Chem., 248:1480-88.

440 BIOGRAPHICAL MEMOIRS With Ta-Hsiu Liao, Johann Salnikow, and Stanford Moore. Bovine pancreatic deoxyribonuclease A. Isolation of cyanogen bromide peptides; complete covalent structure of the polypeptide chain. I. Biol. Chem., 248:1489-95. With Rikimaru Hayashi and Stanford Moore. Carboxypeptidase from yeast. Large scale preparation and the application to COOH-terminal analysis of peptides and proteins. J. Biol. Chem., 248:2296 -302. With Stanford Moore. Chemical structures of pancreatic ribonu- clease and deoxyribonuclease. Les Prix Nobel en 1972, pp. 120-43. Stockholm: The Nobel Foundation, and Science, 180:458-64. With Rikimaru Hayashi and Stanford Moore. Serine at the active center of yeast carboxypeptidase. J. Biol. Chem., 248:8366-69. 1974 With Jacques Bartholeyns and Stanford Moore. A pancreatic ri- bonuclease active at pH 4.5. Int. }. Pept. Protein Res., 6:407- 17. 1977 With Jacques Bartholeyns, Dalton Wang, Peter Blackburn, Glynn Wilson, and Stanford Moore. Explanation of the observation of pancreatic ribonuclease activity at pH 4.5. Int. I. Pept. Protein Res., 10:172-75. 1979 With Stanford Moore. In: 75 Years of Chromatography A Historical Dialogue, ed. L. S. Ettre and A. Zlatkis, pp. 297-308. Amster- dam: Elsevier.

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Biographic Memoirs: Volume 56 contains the biographies of deceased members of the National Academy of Sciences and bibliographies of their published works. Each biographical essay was written by a member of the Academy familiar with the professional career of the deceased. For historical and bibliographical purposes, these volumes are worth returning to time and again.

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