MICROREVIEW

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny

Frieder W. Lichtenthaler[a]

The 150th anniversary of the birth of Emil Fischer, coincidingwith the centenary of his receiving the Nobel Prize in Chem-istry the second ever awarded provides a welcome oppor-tunity to highlight the paramount achievements of thistowering figure of our science. By focussing his research onorganic matter on which the living world is built N-hetero-cycles, carbohydrates, tannins, proteins, and, finally, fats he

1. Introduction

When we look at organic chemistry today and reflect onhow it has developed over the last century, no other organicchemist has been more determining, focussed and inspiringthan Emil Fischer (18521919) (Figures 1 and 2). He notonly pioneered the scientific knowledge on which modernorganic chemistry and much biochemistry is based, but alsoengendered the succeeding generation of scientists.

This year, the 150th anniversary of his birth coincideswith the centennial of his receiving the 1902 Nobel Prize inChemistry the second ever awarded and the first inorganic chemistry.[1] Hence we have a unique opportunitynot only to appreciate this monumental scientific contribu-tions with which he refocussed the thinking on organicchemistry back to its roots, the world of living Nature. The

[a] Institut fr Organische Chemie,Technische Universitt Darmstadt,Petersenstrae 22, 64287 Darmstadt, GermanyFax: (internat.) 49-(0)6151/166674E-mail: fwlicht@sugar.oc.chemie.tu-darmstadt.de

Frieder Lichtenthaler studied chemistry at the University of Heidelberg and received his doctorate therein 1959 with F. Cramer. After three postdoctoral years at the University of California, Berkeley, with H.O. L. Fischer the only of Emil Fischers three sons who survived World War I he joined the facultyof the Technical University of Darmstadt, where he acquired his Habilitation in 1963, was appointedassociate professor in 1968, and full professor in 1972. His research activities, documented in over 270publications, comprise the generation of enantiopure building blocks from sugars, their use in the synthesisof oligosaccharides and complex non-carbohydrate natural products, molecular modelling of chemicaland biological properties of sugars, and studies towards the utilization of carbohydrates as organic rawmaterials.

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not only laid the foundations of organic chemistry and bio-chemistry as we know it today, but through the research edu-cation of 330 doctoral students and postdoctoral associateswho flocked his laboratory from all over the world, hebrought forth the succeeding generation of scientists.( Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim,Germany, 2002)

impact this had on the further development of organicchemistry and biochemistry has been treatedextensively.[219] But it is also timely to remember his vari-ous other achievements, most notably his vital role as a me-diator between science, industry, and government that ledto the foundation of the Kaiser-Wilhelm- (today Max-Planck-) Society, and, not least, the indelible imprint hisstriking personality, his ideas, and his mode of conductingresearch left on his scientific progeny.

2. Fischers Scientific Achievements

Fischers impressive scientific uvre, which made him theunique pioneering figure of his time in organic chemistryand biochemistry alike, is remarkable both in its variety oftopics and its depth. Today, we marvel at his foresight inchoosing his fields of research which were the basic struc-tural and synthetic chemistry of purines, carbohydrates,polypeptides, and fats, i.e. the four kinds of organic matteron which the living world is built. In that, he tackled sub-stances produced by living organisms which are constitu-

F. W. LichtenthalerMICROREVIEWtionally repetitive and were then exceedingly difficult tostudy because of the lack of adequate methods for analysis,separation and synthesis. Thus, he differed markedly fromthe chemists of his time who were working on natural prod-ucts and were occupied with the constitutional analyses andsyntheses of easily crystallizable low-molecular-weight com-pounds. He steered the course of organic chemistryback to its origins, that is the task of studying the majorsubstances of living organisms, thereby contributing greatlyto the outlook of the next generation of organic chemistsand biochemists.

The paramount achievements of Fischers stellar careerof 45 years are set out in his 600 or so experimental papers(Abhandlungen mit experimentellem Inhalt) and 20 lectures,which appeared, with very few exceptions, in Ber. Dtsch.Chem. Ges., Justus Liebigs Ann. Chem., Hoppe-Seylers Z.Physiol. Chem. and Sitzungsber. Preu. Akad. Wiss. Theyhave been collected into a set of eight volumes,[26a26h] eachbeginning with at least one comprehensive review, usually adetailed elaboration of a lecture.

Today, the essence of these prodigious achievements hasnot only entered the textbooks of organic chemistry butalso those of biochemistry. Accordingly, a detailed exposi-tion appears unnecessary here, as accounts of Fischers ma-jor research contributions are readily available, such as onthe unravelment of the sugar configurations,[11,13,27] his con-ventions for projecting stereoformulas into a plane,[28] orthe lock-and-key analogy for the specificity of enzymeaction,[1416] which has provided generations of scientistswith their mental image of molecular recognition processes.Nonetheless, a brief overview of the sequence of Fischersresearch work would seem to be appropriate.

Fischers scientific work began 1873 in Baeyers laborat-ory at Straburg with his investigations of triphenylme-thane dyes which was the subject of his dissertation.[21] He

Emil Fischer was born on 9 October 1852 in Euskirchen, a small town near Bonn. He was the youngest of eight children, two ofwhom had already died. The female dominance of his five older sisters was balanced by five male cousins living next to the tradinghouse Gebrder Fischer, which specialized in experimental dyeing and wool-spinning and was owned by his father and two of hisuncles. After attending elementary school in Euskirchen and secondary schools (Gymnasium) at Wetzlar and Bonn, he obtainedhis Abitur in 1869, at the age of 17, when he was apprenticed to his brother-in-law, a timber merchant, as his father wanted himto enter the family business. This occupation proved uncongenial and, at 19, he was finally allowed to follow his inclination tostudy mathematics, physics, and chemistry at the University of Bonn, where he and his cousin Otto Fischer[20] commenced in thesummer of 1871. Unimpressed by the lectures of Kekule, Zincke, and Kundt (physics), the two cousins moved, a year later, to thenewly established University of Straburg. Here they came under the influence of Adolf Baeyer, who fired their enthusiasm fororganic chemistry. Both young men joined his group and, at the age of 22 (in 1874) obtained their Dr. phil. degrees under hisguidance for work on the structures of phthaleins, newly discovered (E. F.[21]), and the action of chloral on toluene (O. F.). In thesame year, Emil Fischer was appointed assistant instructor in the organic laboratory course, where, by chance, by meticulousobservation, and by keen perception, he turned a students faulty experiment into his own first great discovery, phenylhydrazine.When, in mid-1875, Baeyer moved to Munich as successor to Justus von Liebig, both Fischers joined him. There, Emil continuedhis work on the hydrazines, which became the basis of his Habilitation (1876), carried out extensive investigations on rosanilinedyes with his cousin Otto, and also started work on purines. In 1879, he was appointed Associate Professor of Analytical Chemistry,as successor to Volhard.[22] In the same year, he was offered the Chair of Chemistry at Aachen which he refused; but in 1882 heaccepted an invitation from the University of Erlangen to succeed again Volhard. There he was much preoccupied with theconversion of phenylhydrazine into N-heterocycles. In 1885, he again moved, this time to the University of Wrzburg, at firstcontinuing his work on purines, but then entering the at the time quite desolate state of carbohydrate chemistry. Within theunbelievably short span of seven years he solved the perplexing problem of the sugar configurations work that in 1902 wasrecognized with the Nobel Prize in Chemistry, the second ever awarded. In 1892, on the death of A. W. von Hofmann,[23] Fischer,after some initial reluctance, accepted the invitation to become his successor in Berlin; so by the age of 40 he achieved the mostcoveted academic position in chemistry that Wilhelminian Germany had to offer, which he filled with ever increasing distinctionuntil his death in 1919.

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continued this work in Munich together with his cousinOtto Fischer,[20] resulting from 1876 onwards in 14 jointpublications,[29] which the two young men, although only intheir twenties, were allowed to publish on their own. Theabsence of any acknowledgment to their teacher attestsboth to their independence and to Baeyers apparent esteemand encouragment towards his gifted pupils. Apart fromthis work, Emil Fischer, while in Munich, exploited thechemistry of phenylhydrazine which he had accidentally dis-covered in 1874, while still in Straburg;[30] he prepared thephenylhydrazones of the common aliphatic and aromaticaldehydes[31] and also elaborated the indole synthesis, whichhas come to bear his name.[32]

For nearly ten years he does not appear to have recog-nized the tremendous value of the phenylhydryazine for thecharacterization and identification of carbonyl compounds,until, in 1884, he eventually applied it to the sugars, therebyentering new territory into which few had ventured beforehim. By means of an ingenious series of systematicallyplanned experiments and brilliant reasoning, along withsome serendipity, Fischer unravelled their configurationswithin the course of seven years.[33] This brilliant syntheticand analytical work, and the manner in which he appliedand further developed the vant HoffLe Bel theory forelucidating the stereochemical relationships of the sugarsstands out as the pinnacle of his career. A hundred yearsago, on the occasion of the Nobel Prize being awarded tohim, the President of the Royal Swedish Academy of Sci-ences in his presentation speech expressed his appreciationin the following words:[1]

The specific type of research which has characterized or-ganic chemistry during the final decades of the nineteenthcentury attained its zenith of development and its finest formin Fischers studies of sugars and purines. From the experi-mental point of view they are unsurpassed.

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEW

Figure 1. Photograph of the Baeyer group in 1878 at the laboratory of the University of Munich (room for combustion analysis), withinscriptions from Fischers hand;[24] in the center Adolf Baeyer, to his right the 25-year-old Emil Fischer, in a peaked cap and strikinglyself-confident three years after his doctorate; to the left Jacob Volhard[22] who was in charge of the analytical devision in Baeyers institute,and whose successor Fischer was to become in Munich a year later (1879), and at the University of Erlangen in 1882; sitting left toVolhard Fischers cousin Otto Fischer,[20] with whom he did extensive work on rosaniline dyes;[29] between Baeyer and Volhard standsWilhelm Koenigs who in 1900, together with his doctoral student Eduard Knorr, discovered the Ag2CO3-induced glycosidation of aceto-bromoglucose,[25] known today as the Koenigs-Knorr reaction

This classical work was not the only great service Fischerrendered to chemistry, since later he returned to the workhe had started in 1882 in Munich on purines, which led tothe general classification of this class of substances[26b] and,subsequently, to the synthesis of the first nucleosides.[34]

When the fundamental work in one field was done,Fischer moved on to a new one. In 1899 he started workingon proteins and, during the succeeding ten years, the effortsof his large research group were mainly directed towardsthe study of amino acids, peptides and polypeptides, cul-minating in the formidable synthesis of an octadecapeptidecomposed of 15 glycyl and three leucyl units.[35] The successof these activities, which brought the proteins into the orbitof respectable organic chemistry, fell short of his aims whichwent much further. Indeed a passage from a letter to A.von Baeyer, written at the end of 1905, reads:[36]

My entire yearning is directed toward the synthesis of thefirst enzyme. If its preparation falls into my lap with the syn-thesis of a natural protein material, I consider my mission ful-filled.

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So, around 1910, when his work on the proteins ceasedbecause of insurmountable experimental difficulties at thetime only eight publications out of the total of 147 onthis subject appeared thereafter[26f] he initiated anothersustained and successful research program on lichens andtannins which he termed depsides.[26g] In the final years ofhis life he turned to the synthesis of glycerides,[37] thus add-ing the fats to the classes of chemical constituents of biolo-gical systems, purines, carbohydrates, and proteins, that hehad studied in the 45 years of his scientific career.

3. Fischers Personality and Working Style

Apart from his autobiography,[38] written in 1918 butpublished posthumously in 1922, which covers his life onlyup to about 1905, the number of writings about Fischer islegion.[119,3951] The most valuable are the extensiveHoesch biography[6] and accounts by Ludwig Knorr(1919[2]), Martin O. Forster (1920[5]), Max Bergmann

F. W. LichtenthalerMICROREVIEW

Figure 2. Emil Fischer at 37 (top left), 50 (bottom left), at thecelebration of his 60th birthday (top right) and around 1915[24]

(1930[7]), Burkhardt Helferich (1953[8]), and Karl Freuden-berg (1966[11]), all of whom received their doctorates underFischer in Erlangen (L. K.), Wrzburg (M. O. F.), and Ber-lin. As an authentic picture of Fischers personality and ofthe way in which he succeeded in his monumental achieve-ments is best obtained from accounts of those who wereassociated with him over a longer period or knew him well,thus some of their recollections are cited below.

The salient quality of his life was unswerving singlenessof purpose as a researcher. He possessed a remarkable mem-ory and, despite his constant ailments caused by phenylhy-drazine and mercury poisoning a superhuman capacity forsustained work (Forster[5]).

Phenomenal keenness of mind and flash-like comprehen-sion were characteristic of Emil Fischer. Mere indications suf-ficed to grasp the entire matter in its uttermost significance.He could have taken any other profession, he would have ex-celled in it (Harries[39]).

His amazing successes are particularly startling due to thefact, that they required a minimum of theoretical presupposi-tions, and reached their goal by logical application of the sup-positions available, and by the skilful execution of the experi-ments (Bergmann[7]).

Very early, he developed his characteristic manner ofworking. He worked with many selected co-workers, subordi-nating each individual problem to the clearly envisaged general

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goal, and, thus, worked out the whole. Unlike his teacherBaeyer, who might be compared to the leader of a reconnais-sance patrol with a trained eye for the terrain and the possibil-ities of the pathways, Emil Fischer was the clever tacticianwho proceeded on a broad front, here gaining ground veryquickly, there holding back cautiously, until what lay behindwas all safely in his possession. He knew how to make gooduse of the great advantages of the research programs requiredfor doctoral candidates at German universities. Teamwork, ashe developed it, demands a superior leader. It was magnificentto work under his direction and yet independently; as a re-search instructor, he blazed the trail for the generations suc-ceeding him (Freudenberg[11]).

Physically commanding, his authority rested on the solidfoundation of natural dignity unmarred by self-assertion. Thebrisk, upright carriage marked the man of action; the glowingeyes revealed his attitude of constant, keen inquiry; the impa-tience with trivialities was one aspect of his dominating,steadfast control of essentials. With ordinary human percep-tion, it was impossible for anyone to escape his contagiousenthusiasm, and yet all the time the master did not obscurethe man, for although his daily demeanour was tinged withseverity, his heart when revealed was deeply kind, and, in cir-cumstances of relaxation, joyous (Forster[5]).

A glimpse of the atmosphere in the Berlin institute (Fig-ure 3) has been provided by the American physician JamesB. Herrick, who worked with him in 1905:[52]

Figure 3. Emil Fischer around the turn of the century in his Priv-atlaboratorium at the University of Berlin;[24] the somewhat un-usual laboratory stool he inherited from his predecessor, AugustWilhelm von Hofmann, who, in 1865, brought it to Berlin on hismove from the Royal College of Chemistry, London

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWHe was modest, kindly, always the gentleman. Twice a

day he made the rounds, moving quietly from desk to deskinspecting the work, always seeming interested, criticizing,helpfully suggesting. He had the faculty of seeing quicklywhere ones trouble lay. So gentle in manner was he that onescarcely realized that he was a good executive commandingofficer.

On the other hand, in the recollection of Bergmann:[7]

Fischer was reticent with his co-workers when he gavethem instructions for the conduct of experiments or when hehimself did laboratory work in their presence. Then, an in-dication of the purpose and goal and expected outcome of theexperiment was either not given or stated very incompletely.

These facets of life in Fischers Berlin institute may bebalanced by the testimony of Richard Willsttter, 20 yearsyounger than Fischer, but also from the Baeyer school. In1911, while holding the chair of chemistry at the Swiss Fed-eral Institute (ETH), Zrich, Willsttter had turned downthe offer of the directorship of the Kaiser-Wilhelm-Institutefor Chemistry in Berlin-Dahlem, yet was persuaded byFischer who visited him in Zrich to change his mind(the reverence for the great man played a role when Icomplied):[53a]

Emil Fischer ruled his laboratory with absolute authority.The princely man who gathered about him most of the doc-toral students and other young investigators overshadowedeveryone in greatness, spirit, and scientific insight ... He wasthe unequalled classic, the master of organic-chemical re-search in analytical and synthetic direction.

Another principal feature of Fischers personality was hispronounced aversion to any sort of theoretical speculation.Although his keen intellect was aboundingly endowed to-wards the speculative side, his critical disposition towardsanything that transgressed what could be proved experi-mentally prevented him from communicating speculationsin either word or script.[7] A few examples illustrate this at-titude.

Referring to the question still controversial in 1914 onthe ring sizes of the fructose and glucose portions of sucroseand how these sugars are linked, Fischer, who had estab-lished the basis of carbohydrate chemistry, clearly statedhis position:

We know nothing definite on the mode, how the fructoseresidue is linked in cane sugar, thus leaving huge room forspeculation. I, however, gladly renounce to use it.[54]

A pertinent example is the Fischer lock-and-key analogyof 1894, used alongside his studies on the fermentability ofthe sugars by yeast. Towards the end of his famous paperof 1894 on the Influence of the Sugar Configuration onthe Action of Enzymes,[55] he simply illustrates the resultshe had obtained by using a pictorial analogy:

To use a picture I would like to say that enzyme and gluc-oside have to fit together like lock and key in order to exerta chemical effect on each other.

That this rather incidentally used metaphor was immedi-ately taken up, not only by organic and physiological chem-ists but by medical researchers in particular, obviously sur-prised Fischer. Paul Ehrlich, for example, introduced it

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from 1897 onwards into the then young discipline of im-munology through his so-called side-chain theory of im-munity, which was elaborated in great detail.[56] As thisgreatly transgressed what could be proved experimentally,Fischer already felt in 1898 that he had to state the scopeof his analogy:

As there must be a similarity in the molecular configura-tion between the enzymes and their object of attack, if reac-tion is to take place, I have used the image of lock and keyto make this thought more perspicuous. I am far from placingthis hypothesis side by side with the established theories ofour science, and readily admit that it can only be thoroughlytested when we are able to isolate the enzymes in a pure stateand thus investigate their configuration.[57]

While Ehrlich had brought the lock-and-key conceptfrom the realm of chemical reactions in solution to reac-tions on the cell surface, others extended it to cell-cell inter-actions (e.g. Lillie to fertilization[58]) to try to explain phe-nomena which were much too complex to yield to rational-ization or comprehension at that time. These theories fromEhrlich, Lillie, and others who thought along similarlines,[59] yielded conflicting experimental evidence. Fischerslock-and-key analogy, however, still stands in the annals ofscience, over a 100 years later, as a most fertile concept,because it was unspecified in its details, and thus left ampleroom for the imagination of chemists, biologists, and med-ical researchers alike.

Fischers refusal to make theoretical speculations waseven imposed on his co-workers, with a printed guide forthe conduct of experiments, regularly presented to the olderstudents and to his assistants. This document contained theunequivocal directive:

You are urgently warned against allowing yourself to beinfluenced in any way by theories or by other preconceivednotions in the observation of phenomena, the performance ofanalyses, and other determinations.[7]

In literary style Fischers papers are uncompromisinglyascetic. Each subject is pursued from a deeply perceived,superior point of view, and the treatment, although com-plete, is so concise that a concluding summary of the resultsis unnecessary. Usually though, in a sentence or two, a clearindication is given at the end of the paper of what has tobe done next.

This terse style of writing which undoubtedly was ad-opted by many of his scientific progeny, can be traced backto his first publication on the accidental discovery ofphenylhydrazine in 1875.[30] This paper is unusual in severalrespects: First, Baeyer, allowed him to publish it independ-ently without even an acknowledgment to his teacher, at-testing to the high esteem Baeyer had for his gifted pupil.Secondly, the paper is formulated in an unusually concise,clear style and written in the first person:

I have again taken up experiments on the reduction ofdiazo compounds. ... I arrived at a class of well-characterizedbases, for which I propose the name hydrazine compounds.[30a]

A rather self-confident statement for a young chemist of23 who had just received his doctorate, and the more so,

F. W. LichtenthalerMICROREVIEWsince the parent compound, hydrazine, was to be discoveredonly twelve years later.[60] Reading today Fischers paper of1875 which unknowingly at the time of its publication contained the key for his later elucidation of the sugarconfigurations,[13,27] engenders the sensation of sitting at themodest source of what was to become a mighty river withinthe next 45 years.

Of the nearly 600 experimental papers that were tofollow, 185 appeared under his sole authorship, givingcredit therein to the co-worker(s) only by an acknowledg-ment. For example, the two co-workers Dr. W. Axthausenand Dr. H. Tappen who performed the tremendous experi-mental work in the formidable synthesis of an octadecapep-tide, are merely thanked for their valuable help in the lastsentence of the paper.[61] Even more curious in this context,a total of 92 papers were published under the sole author-ship of his doctoral students, representing limited extractsfrom their dissertations with elaborate experimental details,but scant discussion. Each paper, inevitably, bore the intro-ductory phrase On the instigation of Professor EmilFischer I have investigated ....

4. Fischer and the Chemical Industry

Fischers probably greatest and most direct contributionto chemical industry lies in the stream of young chemistspassing regularly from his laboratory to the factories, mensoundly trained in the methods of systematic inquiry andinspired by the imposing example of their teacher whichhad established their devotion to chemistry. Fischers per-sonal relationship to the chemical industry was initiated bythe interest the tar-dye factories had in his early work withhis cousin Otto on fuchsine and rosaniline dyes[29] whichhad generated a demand for his expertise to such an extent,that at the relatively young age of 31 he just had resumedhis professorship at the University of Erlangen the Badis-che Anilin- und Soda-Fabrik (BASF) offered him the posi-tion of director of research, in succession to Heinrich Caro.But Fischer declined the offer despite a most attractive sal-ary for that time (1883) of 100000 marks,[40] because inhis own words[38a] full freedom in scientific research wasmore appealing to me. However, I accepted the invitationfor a three-week stay, in which I was shown the entire fact-ory and took the opportunity to use the technical laborat-ory for methylating large amounts of uric acid, which wereneeded for further investigations in the purine series. Thesame attitude prevailed much later in his life, e.g. in Febru-ary 1919, when Bayer Leverkusen wanted to elect him toits board. His response was unequivocal, as he wrote in aletter to Carl Duisberg:[62]

Prussian jurisdiction prohibits to be a member of a profit-oriented enterprise while still being in office. Although thereare some exceptions, it is better that I still be considered as

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a sort of confidant between administrative authorities and in-dustry.

An industrial connection with Farbwerke Hoechstemerged from a product, dimethyl-phenyl-pyrazolinone,which was prepared by his then assistant Ludwig Knorrfrom phenylhydrazine and ethyl acetoacetate and sub-sequent methylation. It proved to have excellent analgesicand antipyretic properties and was marketed by Hoechstunder the name antipyrine. Various analogues of similar ac-tivity, such as the highly successful pyramidone, were sub-sequently developed by Knorr and the Hoechst laborat-ories.

A highly profitable industrial involvement originated in1902 from Fischers joint work on diethyl barbituric acidwith J. von Mering, Professor of Medicine at Halle Univer-sity.[63] This substance proved to be a highly effective sopor-ific that Fischer used successfully even on himself.[64] Afterobtaining the patent rights,[65] diethylbarbituric acid wasfirst produced by Merck at Darmstadt, and then, from 1904onwards, jointly with Bayer Leverkusen, becoming underthe name veronal (or barbital) one of the most valuablehypnotics. In later joint research with von Mering (1907)calcium iodobehenate (sajodin), a tasteless iodine sourcereadily tolerated by the organism, was manufactered by theBayer and Hoechst companies. Another pharmaceutical linebegan in 1913, when Fischer collaborated with G. Klem-perer, chief physician of the Moabit Hospital in Berlin andcancer expert,[66] in the evaluation of certain arsino- andseleno-behenolates which he had prepared as carcinomaremedies.[67] One of these, Elarson was marketed by Bay-ers Elberfeld factory.

Fischers intense interaction with the chemical industry isdocumented in great detail by his immense correspondencewith essentially all of the major companies in Germany andtheir principal leaders. The Emil Fischer Papers[68] contain181 letters from Carl Duisberg, (covering the years18951919), from Farbenfabriken Bayer (271), Hoechst(50), Boehringer Mannheim (116), BASF (54), MerckDarmstadt (33), and various others, their content delineat-ing the multifaceted interrelationships between academeand the chemical industry, which would be well worth acomprehensive evaluation.

Whilst these close relationships with the chemical indus-try arose from Fischers academic research, the outbreak ofWorld War I in 1914 generated very different demands,which were to dominate the years destined to be theclosing period of his life. Because of his outstanding reputa-tion, his comprehensive technical knowledge, his organiza-tional skills, and his extensive experience in coordinatingscience and industry, the German government asked him tomediate between the military and industry.[41,45,46,69] He wasappointed to head various government commissions, suchas the Commission on the Supply of Coke Products thatwas set up to address the sudden increase in demand fortoluene and heavy oils. Notably, he headed the SaltpetreCommission, set up to boost production of synthetic salt-petre by oxidation of ammonia from the Haber-Bosch pro-cess, an urgent necessity due to the interruption of Chile

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWsaltpetre imports by the sea blockade. Fischer succeeded inbringing all men together required for the solution of theseproblems, particularly the industrial leaders in the Rhineand Ruhr districts and moulded a joint effort towards theestablishment of various new production sites, and this suc-cessfully overcame these shortages.[41] Other war-relatedprojects which he either directed himself or played an activerole in, were the utilization of the sulfur in gypsum (CaSO4)and kieserite (MgSO4) in substitution for the diminishingsupplies of pyrite (Gips- und Kieserit-Kommission), theexploration of alternative sources for glycerol, the substitu-tion of camphor in gunpowder stabilization by dimethyl-and dimethyl-diphenyl-carbamide, the conversion of strawand wood into digestible fodder for cattle (Nhrstoffaus-schu), and the enhancement of nitrogen fertilizer produc-tion. In view of these unusually diverse activities, the acutephysical pain that tormented him from time to time, theloss of his second and third sons in 1915 and 1917, and thedeath of scientific workers in his institute due to their milit-ary service, it is outright amazing that he found time tocontinue his scientific research. Or did he rather take refugeto it? It was during this period that his work on depsidesreceived many decisive additions and that the study of fatswas started, probably as a result of his involvement in theWar Commission on Oils and Fats. Whatever the case,an abundance of new ideas and observations appeared inthe 30 publications written in that time.

5. Fischers Role in the German ChemicalSociety

The position Emil Fischer occupied in Berlin meant thathis activities went far beyond his institute and his science.He was four times President of the Deutsche ChemischeGesellschaft (1894, 1895, 1902 and 1905) and Vice presidentno fewer than eight times, though the fairly extensive ad-ministrative work was somewhat eased because his prede-cessor, A. W. von Hofmann, who had founded the Societyin 1867, had located both its secretariat and the editorialoffice for the Berichte it issued in the Chemical Institute;this situation lasted until completion of the Societys ownbuilding, the Hofmann-Haus, in 1901.[38b,42,70] DuringFischers presidencies, some basic changes in the structureand organization of the society were effected, most notablythe expansion of its literary tasks by taking over the pub-lication of the third and supplement editions of BeilsteinsHandbuch fr Organische Chemie and the Chemisches Zen-tralblatt in 1895 by means of acquiring the respective pub-lishing rights. These actions were driven through againstconsiderable opposition, and yet proved to be opportune, asthe number of subscribers roughly tripled, and the chemicalindustry honoured the new enterprises by making substan-tial donations.[38b,42]

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A rather odd incident, known as The RamseyCase,[6d,71] in which Fischer played a decisive role, is worthmentioning. Ramsay, who had been awarded the NobelPrize in Chemistry in 1904 for the discovery of inert gas-eous elements in air, had studied in Heidelberg withBunsen and in Tbingen with Fittig (Dr. phil. in 1872), hadbeen elected an honorary member of the German ChemicalSociety in 1899 (on the proposition of Fischer). He receivedits Hofmann Medal in 1903, and furthermore was awardedthe Prussian order Pour le Merite in 1911. However, atthe beginning of World War I, he violently attacked Ger-man science and the entire German race which aroused therage of his German colleagues to the extent that, in April1915, at the general assembly of the Society, a strong fac-tion demanded the removal of Ramsays name from the listof honorary members. In the hot-tempered discussion,Fischer vehemently took the opposite standpoint,[71] sayingthat Ramsay discovered the noble gases and is one of themost outstanding chemists of all time, irrespective of thewar in which our peoples are engaged,[6d] and, mainly bythe impact of his strong personality, he managed to achievea compromise: Ramsay was to be given the opportunity tojustify his actions after the war. This never came about, asRamsay died in 1917. The Chemical Society (London) inits turn was less restrained on these matters, as Emil Fischer together with Adolf von Baeyer, Walter Nernst, WilhelmOstwald, Otto Wallach, and Richard Willsttter[72] wereremoved in 1916 from the list of Honorary and ForeignMembers.[71]

Fischer also played a very active role in the PrussianAcademy of Sciences in Berlin, to which he had beenelected in 1893.[73] Apart from participating in all its meet-ings, the Academy required from its members the presenta-tion of a comprehensive lecture each year, so it can be safelyconcluded, that of the 26 lectures Fischer was obliged todeliver, a major portion entered into the well-elaborated lec-tures that appeared in print.[26h]

6. Emil Fischers Activities in Establishing theKaiser Wilhelm Society and Its Institutes

Science is not to be understood as an autonomous devel-opment determined by immanent laws or inherent lo-gic of the respective subject areas. The major contributoryparts are specifically cultural, political, industrial and otherexogenic factors. In this context, we may recall that Fis-chers influence far exceeded his scientific work and its mat-erial consequences. Indeed, it was largely due to his inspira-tion and untiring energy that the idea of establishing a re-search foundation, independent of teaching duties, ulti-mately took shape and came to be realized in thefoundation of the Kaiser-Wilhelm-Gesellschaft in1911.[7477] The opening of the first institutes was cele-

F. W. LichtenthalerMICROREVIEWbrated in October 1912 (cf. Figure 4): the Kaiser-Wilhelm-Institute fr Chemie at Berlin-Dahlem, with ErnstBeckmann and Richard Willsttter as its leading figures,and the KWI fr Physikalische and Elektrochemie with FritzHaber as its director. Others were to follow, most notablythe KWI fr Kohlenforschung in Mlheim/Ruhr, a joint en-terprise of government, chemical industry and the city ofMlheim, and it was Fischer, with his authority, persuasivepower, and diplomatic skills, who united these disparatefactions into contributing substantial funding towards acommon goal. Furthermore, in a 1912 lecture at SolbadRaffelberg near Mlheim entitled Augmentation of the In-trinsic Values of Coal[78] Fischer even determined in astroke of prophetic foresight the research programme tobe pursued: improvement of the coking process, the genera-tion of synthetic rubber from coking gases, the productionof liquid and gaseous fuels by use of catalysts, and the dir-ect generation of electricity from coal. The KWI for CoalResearch was opened in July 1914, four days before the out-break of World War I, and these tasks set by Fischer wereall tackled and scientifically solved during the war whilsttheir large-scale industrial realization started later. In 1925,the production of liquid fuel from coal (Fischer-Tropschsynthesis) was achieved, the catalytic processes reaching aclimax with the work of Karl Ziegler on the metal-catalyst-induced normal-pressure polymerization of ethylene.

Figure 4. Kaiser Wilhelm II at the inauguration of the first twoKaiser-Wilhelm-Institutes (for Chemistry, and for Physical Chem-istry and Electrochemistry) in Berlin-Dahlem on 23 October1912;[24] behind the emperor, the president of the Society, Adolfvon Harnack (right), and Emil Fischer (center), its vice-president

7. Fischers Scientific Progeny

The most advanced discoveries of any age constitute thebasis for next. Where Fischer left off, his scientific progenycontinued. Thus, Fischers impact on the subsequent devel-opment of organic chemistry and biochemistry derived notonly from his monumental research achievements, but alsofrom the experience gained by his doctoral students, post-doctoral associates and research assistants. Some 330[79] sci-

Eur. J. Org. Chem. 2002, 409541224102

entists from all over the world crowded into his laboratories,first at Erlangen but then in greater numbers at Wrzburg(18881892) and, over the next 26 years, at the Friedrich-Wilhelms-Universitt of Berlin (now Humboldt Univer-sity).

The Fischer School was formed principally from studentswho joined his research group to work for their doctorates(223), of whom a sizeable number (46) were from foreigncountries, most notably from the U.S. (21) and Great Bri-tain (18). Thus, the greater part of the outstanding workFischer brought forth during his scientific career of 45 yearswas, in fact, carried out by doctoral students. Their effici-ency in tackling the research topics assigned to them re-quired a superiour research instructor, who knew how tomake good use of the advantages of the research pro-grammes required for doctoral candidates at German uni-versities. Of Fischers 108 remaining postdoctoral associatesabout one-third (38) had received medical degrees, and from 1902 onwards, when Abderhalden, himself Dr. med.,had joined Fischers group as Privatassistent the medicalmen were routinely allocated to Abderhalden for work onthe amino acid analysis of proteins.

Most of Fischers students and associates found employ-ment in the chemical industry or government offices, someattaining high office in such chemical firms as Boehringer-Mannheim or Hoechst. Fischers greatest contributions tothe subsequent later development of the chemical and bio-chemical sciences derive from the work of his students andassociates who remained in academic life or entered scient-ific research institutions. These workers, 112 in all, comprisesome of the most distinguished chemists and biochemistsof the 20th century. The genealogical tree of Figure 5 showstwenty Fischer Schler who achieved particular scientificdistinction in their later careers, both as leaders of product-ive research groups and as teachers. Four of those OttoDiels, Hans Fischer, Fritz Pregl and Adolf Windaus re-ceived the Nobel Prize for Chemistry, two others, KarlLandsteiner and Otto Warburg, for Physiology or Medicine.

The first of the pre-eminent Fischer Schler, whose laterwork was clearly derived from his mentors line of research,was Ludwig Knorr [18591921][80] (Figure 6). His associ-ation with Fischer began in Munich and continued in Er-langen, where he obtained his doctoral degree (1882) andhis Habilitation (1885). Thence, he moved to Wrzburg,where he became head of the inorganic section. Knorrs dis-sertation dealt with piperylhydrazines, work that he was al-lowed to publish on his own.[81] Shortly afterwards, in 1883,the reaction of phenylhydrazine with ethyl acetoacetate ledhim to a pyrazole derivative[82] that proved to be a veryeffective antipyretic and analgesic. Here, too, Fischers lib-erality to take the credit for results of research he had him-self initiated, was amazing, since he permitted Knorr to ob-tain a patent on his own account. The product, called anti-pyrine, later phenazone, was manufactured by theHoechst dyeworks and this, together with a later andmore effective analogue, pyramidone became the thenleading antipyretic and analgesic. This also marked theentry of a dyestuff company into the pharmaceutical indus-

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEW

Figure 5. Emil Fischer as the founder of a great scientific tradition; his example and importance shows organic chemistry to be at thebasis of biological, medicinal, and clinical chemistry through his scientific progeny; six of these developed fields which subsequentlygenerated Nobel Prizes (names and year of award indicated by shading); amongst the following generation, i.e. Fischers grandchildren,were some of the most distinguished chemists and biochemists of the 20th century, of whom nine received Nobel Prizes for their scient-ific achievements

Eur. J. Org. Chem. 2002, 40954122 4103

F. W. LichtenthalerMICROREVIEW

Figure 6. Ludwig Knorr

try.[83] In 1889, Knorr became professor of chemistry atJena, where over the years he directed a large researchgroup. His major achievements were his outstanding studieson pyrazoles and pyrroles (Knorr pyrrole synthesis), onalkaloids related to morphine and on the keto-enol tauto-merism in 1,3-dicarbonyl compounds, in which H. O. L.Fischer (Dr. phil. 1911) participated,[84] as his father didnot want to do his doctoral work under his supervision.[85]

Oskar Piloty [18661915][86] (Figure 7) was long associ-ated with Fischer (18881900), first in Wrzburg where heparticipated in the experimentally difficult studies on sugarsby preparing higher homologues of rhamnose [87] and re-duction products of saccharic acid[88] work which gainedhim the Dr. phil. degree in 1890. He continued as Fischersresearch assistant, and moved with him to Berlin in 1892 tohead the inorganic section and there became heavily in-

Figure 7. Oskar Piloty

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volved in the work for constructing a new chemical insti-tute. As Harries later noted:[86] He was one of the paladinsof Emil Fischer who helped him to accomplish his greatachievements. Pilotys independent career started promis-ingly with studies on aliphatic nitroso compounds, which in1898 led to his habilitation. In 1900, he accepted an associ-ate professorship of inorganic chemistry in Baeyers insti-tute in Munich, where he engaged in studies on the consti-tution of the blood pigment, leading to many valuable con-tributions to pyrrole chemistry, from which the later investi-gations of Hans Fischer profited immensely. At theoutbreak of World War I, Piloty volunteered for the army,despite of being over the age of compulsory military service.He was made a company commander, and died in actionin 1915.

From among the 17 research students who had workedwith Piloty during his abruptly terminated scientific career,three attained particular importance as professors at univer-sities and as outstanding researchers, curiously enough inthe field of inorganic chemistry: Otto Ruff [18711939],[89]

Alfred Stock [18761946],[90] and Wilhelm Schlenk[18791943].[91] All three were, in one way or another,closely connected with Emil Fischer, Schlenck even suc-ceeding Fischer in 1921.

Otto Ruff, having obtained his Dr. phil. degree with Pi-loty in Berlin (1897) for work on aliphatic nitroso com-pounds,[92] then joined Fischer in his work on sugars.[93]

When starting out independently, Ruff chose to work oncarbohydrates. Immediately, he discovered the still mostuseful method for shortening the carbon chain of a sugar,simply requiring oxidation of an aldonic acid salt with hy-drogen peroxide in the presence of ferric acetate a pro-cedure that entered the literature as the Ruff degrada-tion.[94] It is much simpler than the one by Wohl,[95] alsodeveloped in Fischers institute, which involves the removalof cyanide from acetylated aldononitriles in a retro-cy-anohydrin synthesis fashion. The decisive turning point inRuff s career occurred in 1902, when Fischer offered himthe position of head of the inorganic section of the newinstitute on condition that he devotes himself solely to inor-ganic chemisty both in teaching and research. Ruff adjustedeasily to this self-denying ordinance and started his success-ful 40-year encounter with inorganic chemistry.[89]

The career of Alfred Stock was also predetermined byEmil Fischer because following his Ph. D. with Piloty onbromination products of acrolein (1899),[96] Fischer gavehim an assistant position, and, a few months later, sent himfor a year (with a Prussian fellowship, yet retaining his Ber-lin salary) to the leading inorganic chemist of the time,Henri Moissan,[97] in Paris. There, Stock was assigned thetask of preparing boron and silicon, both unknown at thetime, yet nonetheless he succeeded in making two siliconborides.[98] Later, outstanding studies on these two elementsestablished Stocks scientific fame.[90] Even Fischer acknow-ledged this work in his biographical memoirs as mostbeautiful achievements in this field.[38c] There, he also re-marked laconically that doing his doctoral thesis in or-

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWganic chemistry was not detrimental to his experimentaleducation.

Carl Harries [18661923][99] (Figure 8) obtained his Dr.phil. degree when working with Tiemann at Berlin in 1890,and then became an assistant in the experimental lecturesgiven by A. W. von Hofmann. In that year, Fischer gave alecture in Berlin on his work on sugars,[100] which must havedeeply impressed Harries, as he later wrote: I never haveheard a better lecture in form and content, full of passionand noble restraint; the really great researcher emerged. Forus, Emil Fischer became the criterion for all other personal-ities.[39] When two years later, in 1892, Fischer succeededvon Hofmann in the chair of chemistry at Berlin, he re-tained Harries as assistant for his own experimental lecturecourses, and, soon realizing his talent, advised him to doindependent research and strive for his Habilitation. Thishe achieved in 1897 with his stereochemical investigationsin the piperidine series,[101], to be followed by his appoint-ment as section head of the Institute in 1900. Their twelve-year association led even to a joint paper dealing with animproved apparatus for vacuum distillation applicable evento methyl glucoside and rubber.[102] Their relationship wasnot without tension though as Harries remarked: In lateryears there developed an ever-stronger estrangement be-tween Fischer and me, which I sincerely regretted. However,I could not change our relationship without giving up someof my rights.[39] Nevertheless, he could always count onFischers encouragement and advise, such that Fischerwrote in his memoirs:[38d] Through the continuous per-sonal and scientific relationship we had over the years, hehas surely learned so much from me, that he may becounted as one of my pupils. In 1904, Harries acceptedthe chair of chemistry at the University of Kiel where his

Figure 8. Carl Harries

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extensive studies on the ozonization of olefins and rubberin particular won him wide acclaim.

By contrast, Karl Landsteiners [18681943][103] (Figure9) association with Emil Fischer was relatively brief. Afterreceiving a Dr. med. degree in his native Vienna in 1891 hespent the next five years in organic-chemical labora-tories, in Fischers Wrzburg Institute doing research onglycolaldehyde, the key intermediate in the generation ofmonosaccharides in the formose reaction.[104] He alsoworked with Bamberger in Munich and with Scholl inZrich on organic topics[105] before embarking, after his re-turn to Vienna in 1896, on his memorable research in im-munology. This work led to the discovery of the human-blood groups (1901) and their classification into the well-known subgroups (1909). In 1922 he moved to the Rocke-feller Institute of Medical Research, were other former EmilFischer associates, such as P. A. Levene and W. A. Jacobs,were already working and Landsteiner continued to invest-igate blood groups and the chemistry of antigens, antibod-ies, and other immunological phenomena, such as the Rh-factor in blood. These monumental achievements were re-cognized by the Nobel Prize in Physiology or Medicine in1930. It was one of his great merits to have introducedchemistry into the service of serology, only possible for aman thoroughly trained in preparative organic chemistry.

Figure 9. Karl Landsteiner

Otto Diels [18761954][106] (Figure 10) was associatedwith Fischer for the unusually long period of 20 years(18961916) which indelibly marked his later most success-ful career. After studying chemistry at Berlin University, hejoined Fischers group as a research student and gained hisDr. phil. degree in 1899 for work on cyanur compounds.He published his dissertation under his sole name,[107] yet itbore the unmissable words at the instigation of ProfessorEmil Fischer in the introduction. Promoted to assistant,he began independent work, leading to his Habilitation in1904 and to his appointment as section head in 1913. Dur-

F. W. LichtenthalerMICROREVIEW

Figure 10. Otto Diels

ing this time Diels discovered carbon suboxide and workedon a variety of other topics including the chemistry of cho-lesterol (with Abderhalden) studies he continued at theUniversity of Kiel on moving there in 1916 as successor toHarries. There, he made decisive contributions to the elu-cidation of the structure of the steroid nucleus by introdu-cing the selenium dehydrogenation as an extremely usefultool (1927) and, in 1928, in collaboration with his doctoralstudent Kurt Alder [19021958] discovered the reactionwhich bears their joint names and for which they wereawarded the Nobel Prize in Chemistry in 1950.

Adolf Windaus [18761959][108] (Figure 11) originallystudied medicine at his native city of Berlin, passing thePhysikum in 1897, but Emil Fischers lectures on chemistryaroused his enthusiasm for the subject, convincing him thatthis was the science for which I am best suited.[109] Con-tinuing his studies in Freiburg, he switched to chemistry,joined the group of Kiliani, and received his Dr. phil. degreein 1899 for studies on the cardiac poisons of digitalis. Win-daus spent the following two years in Fischers laboratoryworking on quaternary aniline homologues.[110] He then re-turned to Freiburg to begin work on sterols, at Kilianissuggestion. This was particularly appropriate, as KilianisInstitute for Medical Chemistry was affiliated with the med-ical faculty. On Cholesterol was the short title of thethesis that gained him his habilitation in medicine (1903).The most remarkable achievements of his 45-year active ca-reer (from 1915 on as director of the Whler-Institut inGttingen) was his intercorrelation of steroids with bile ac-ids by transforming cholesterol into cholanic acid (1919)and by demonstrating (together with the New York physi-ologist Alfred F. Hess) that vitamin D can be producedfrom yeast ergosterol through irradiation with ultravioletlight (1927). Another productive investigation was that ofimidazole, involving the elaboration of the structure of his-

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Figure 11. Adolf Windaus

tidine and the discovery of histamine. In 1928, these notableachievements were recognized by the award of the NobelPrize in Chemistry. Another major contribution to the ad-vancement of chemistry was his establishment of an out-standing research school, from which an unusually highproportion of graduates chose academic careers (cf. Figure5), thereby providing some of the most distinguishedteachers and researchers of the next generation.

Of very a different nature was Hermann Leuchs[18791945][111] (Figure 12). In his memoirs, Fischer de-scribed him as having[38e] a quiet scholarly personality,characterized by discretion, calm and seriousness. He car-ried out the work for his doctoral thesis under my directionon the synthesis of oxyamino acids, the most beautiful re-sult being the synthesis of serine and glucosamine. The skilland conscientiousness which he showed, induced me to se-lect him as private assistant in the difficult investigations onpolypeptides. ... He is a very intelligent chemist and exceed-ingly skilful in experimentation. After two years of excellentwork, he became a teaching assistant, and section headafter Diels move to Kiel. I hope he will obtain an inde-pendent position in the not too distant future. This highlyappreciative opinion of Fischer was a most adequate por-trait of Leuchs at the time, and, indeed, his academic careerbegan promisingly. He received his Dr. phil. degree in1902,[112] his independent status from 1904 onwards, Privat-dozent (1910) and associate professor (1914). He discoveredthe N-carboxyanhydrides of amino acids, made basic con-tributions to the chemistry of spiranes, and, in 1908, startedhis extensive investigations on strychnos alkaloids describedin over 120 publications.[111] For reasons not apparent even

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWto his closest associates he turned down offers of full pro-fessorships at the Universities of Graz and Braunschweig,which would have considerably improved his position, infavour of a personal full professorship at the Berlin Insti-tute. He ended his life during the fall of Berlin in the finaldays of World War II.

Figure 12. Hermann Leuchs

Among those who worked with Fischer, Emil Abder-halden [18771950][113] (Figure 13) occupies a special posi-tion. Having obtained a Dr.med. degree from the Universityof Basel in 1902, he joined Fischers research group at atime when it was principally engaged in work on aminoacids and peptides, first as assistant in his private laborat-ory, then increasingly as supervisor to the succession ofpostdoctoral medical men who flocked Fischers laboratoryfrom all over the world. To them, invariably, was assignedthe determination of the amino acids contained in variousproteins by the ester method, that is conversion of aminoacid mixtures from protein hydrolysates into esters followedby distillatory separation. Although long-winded and notvery original, a large number of publications resulted there-from (ca. 100) providing a first, albeit qualitative, overviewof the amino acid composition of a large variety of proteins.Together with work on proteolytic enzymes, this led to hisHabilitation in 1904 and a professorship at the Berlin veter-inary school (1908). In Berlin, and from 19111945 as pro-fessor of physiological chemistry at the University of Halle,Abderhalden continued with the research topics to whichhe had been introduced by Fischer, particularly in the ap-plication of the halogenoacyl halide method for the assem-bly of polypeptides a nonadecapeptide of questionablepurity, by todays standards, was synthesized in 1912. Bycontrast, Fischer had ceased to use this procedure after1910, realizing that it would not lead to the synthesis of thenatural proteins he was heading for. Extensive work wasalso invested into proving the likelihood of the occuranceof diketopiperazines (cyclic dimers of amino acids) in pro-teins, one of Fischers suggestions which he had not ex-plored further. The formation of diketopiperazines on hy-

Eur. J. Org. Chem. 2002, 40954122 4107

drolysis of silk fibrin, which was taken as evidence that theyare structural elements of the protein,[114] was shown laterto be an artefact arising from the method of preparation. Inaddition to extensive studies on the chemistry of proteins,Abderhalden worked on a variety of biochemical subjects,such as enzymes, protein metabolism, hormones, and vit-amins. His claim, in 1907, to have discovered the so-calledAbwehrfermente eventually aroused much controversy.These were protective enzymes formed upon administeringparenteral protein into the blood plasma and were said tobe capable of degrading the injected protein only.[115] Al-though Michaelis in 1914 and van Slyke in 1916 were un-able to reproduce the experiments, for the next 35 yearsAbderhalden carried out extensive studies to prove their va-lidity.[116] A brief renaissance of the Abwehrferment-Reak-tion ensued in the 1950s with the introduction of the Nie-hans cellular therapy, though it was soon clinically re-futed[117] and finally buried in 1998.[118] Abderhalden wasendowed with seemingly inexhaustible energy, and not onlyproduced over 1200 scientific papers,[119] but also numerousbooks which he either edited or wrote himself. To give threeexamples, his Lehrbuch der physiologischen Chemie (1906)was translated into English and Russian and went through26 editions in 42 years, and he edited the BiochemischesHandlexikon (14 vols.) and the Handbuch der biologischenArbeitsmethoden (107 vols.). In addition, from 1931 to 1950Abderhalden served as President of the German Academyof Natural Scientists Leopoldina in Halle.[113b]

Figure 13. Emil Abderhalden

When Fritz Pregl [18691939][120] (Figure 14) joinedFischers laboratory in 1905, he held a Dr. med. degree fromthe University of Graz, and had already habilitated inphysiology with studies on the C/N ratio in human urine.Accordingly, as a matter of routine, he was turned over to

F. W. LichtenthalerMICROREVIEW

Figure 14. Fritz Pregl

Abderhalden for work on the amino acid composition ofegg albumin and the characterization of certain amino acidderivatives in urine. Whilst his stay in Berlin lasted less thana year, his work generated two publications,[121] and he al-ways emphasized that his chemical research with Fischerand the stimulus of working in Fischers laboratory werethe most valuable influences on his life.[120a] Upon returningto his native Graz, Pregl began investigating the compo-nents of albumins and the analysis of bile acids. However,shortages of starting materials compelled him to developmethods that used smaller amounts for quantitative ele-mental analysis. In 1917 he had devised a series of new in-struments, including a sensitive microbalance, and propertechniques for the analysis of 23 mg samples. Recognitionfor this most significant technical advance in micro-analyt-ical methodology not a discovery, but the ingenious per-fection of existing methods led to the award of the NobelPrize in Chemistry in 1923.

Among Fischers foreign research fellows in Berlin werefive Japanese who all pursued academic careers after re-turning to Japan.[122] The most prominent was Umetaro Su-zuki [18741943].[123] Having studied agricultural chem-istry at Tokyo University, where he obtained a Dr.agr. de-gree in 1901, he spent the next five years in Europe, firstwith Bamberger at Zrich working on plant alkaloids, and,from 1903 to 1905, with Fischer in his Berlin Institute.There he took part in the work on amino acids and poly-peptides, which led to four joint papers.[124] When Suzukileft Berlin at the end of 1905, Fischer advised him, thatback in Japan he should work on research topics that aregenuinely Japanese. Taking this advice, Suzuki began stud-ies on the nutritional values of polished and unpolished rice

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and found that consumption of the former led to nutritionaldeficiencies (beri-beri) in chickens. Having been appointedto a full professorship at Tokyo University in 1907, in 1911he succeeded in isolating a crude substance from rice bran,which proved to be an effective anti-beri-beri factor.[125]

This was marketed by Sankyo Co. in 1912 for therapeutictreatment of beri-beri disease. The active principle, vitaminB1 or thiamine, was also isolated in 1911 by Casimir Funkat the Lister Institute in London,[126] yet despite substantialresearch efforts in many laboratories, it was another 25 ye-ars before Williams succeeded in elucidating its struc-ture.[127] Suzuki continued his research on rice constituents,isolating for example, phytin from rice bran as well as phy-tase, which was the first phosphorylating enzyme to be re-ported. Valuable further contributions resulted from hisextensive studies on vitamin B6 and other natural products.The hitherto unknown amino acids -citrulline, -canavan-ine, and food constituents such as tea catechines, were allisolated by people connected with Suzuki. In 1924 hefounded the Agricultural Chemical Society of Japan,[128]

served as its first president, and became chief researcher ofthe National Physical and Chemical Institute (RIKEN). Hereceived many honours, among them the Imperial Awardof Japan (1924) and the Order of Cultural Merit (1943).When he had the privilege of presenting a lecture to Em-peror Hirohito, he, signally, chose to talk about EmilFischer and biochemistry. In 1993, fifty years after hisdeath, a conmemorative postage stamp (cf. Figure 15) wasissued by the Japanese Government depicting aside Suzukithe (partially hidden) formula of vitamin B1.

Figure 15. Umetaro Suzuki

Among the distinguished biochemists emerging from Fi-schers school, Otto Warburg [18831979] (Figure 16) is es-pecially outstanding[129] as his work during the 1930s rep-resents a peak of biochemical achievements in the 20th cen-tury. He studied chemistry at the University of Berlin andgained his Dr. phil. degree in 1906 for work with Emil

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWFischer on the synthesis of a series of peptides.[130] He thengave up preparative organic chemistry entirely as his inter-est in medical problems led him to study medicine at theUniversity of Heidelberg, where he obtained a Dr. med. de-gree in 1909 for work with Ludolf von Krehl on the respira-tion of sea urchin eggs. Throughout his life he acknow-ledged the importance of his association with Fischer whichhad given him the foundation for his later successes. Indeed,Fischer, as vice-president of the Kaiser Wilhelm Society,was responsible for Warburgs appointment as head of thelaboratory of the Kaiser-Wilhelm-Institut at Berlin-Dahlemin 1914, where he was to conduct his important researchesfor the next 55 years, interrupted only by four years militaryservice during World War I. Around 1920, he resumed hisstudies on cellular respiration, particularly concerning theoxidative metabolism and glycolysis of tumour cells. Healso initiated investigations on the assimilation of carbondioxide in plants, and on the nature of the oxygen transfer-ring respiratory enzyme (the Atmungsferment, i.e.cytochrome-c oxidase). Indeed, brilliant studies earned himthe Nobel Prize in Physiology or Medicine in 1931. His laterresearches, since 1931 as Director of the Kaiser-Wilhelm-Institut fr Zell-Physiologie in Berlin, led to the discoveryof the first flavoproteins and the proof that flavin and nicot-inamide are the active groups of the hydrogen-transferringenzymes, thereby providing, together with the iron oxy-genase discovered earlier, a remarkable account of the ox-idation and reduction processes in the living world.

Figure 16. Otto Warburg

The scientific stature of Hans Fischer [18811945][131]

(Figure 17) was rather different, as his independent careerstarted at a Medical Clinic and his research moved straight-forwardly into the core of synthetic organic chemistry. After

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studying chemistry at Marburg (Dr. phil. in 1904 withZincke) and medicine at Munich (Dr. med. 1908), he be-came a research assistant of Emil Fischer in Berlin, workingon glycosides of lactose and maltose.[132] As early as 1910,however, he terminated his association with Emil Fischer,returned to Munich and, on the advice of the distinguishedclinician Friedrich von Mller who had reasoned that bilepigments are formed from hemoglobin, Hans Fischer beganinvestigating the constitution of the blood pigments in alaboratory of the second medical clinic. He obtained hisHabilitation in 1911 in medicine and succeeded Windausat Innsbruck (1916), Ludwig at Vienna (1918), and finallyHeinrich Wieland in the chair of chemistry at the TechnicalUniversity of Munich (1921). His outstanding achievementsthere over a 20-year period reached their zenith in the totalsyntheses of hemin (1929), for which he was awarded theNobel Prize in Chemistry in 1930, and of bilirubin (1934)as well as extensive studies on chlorophyll, which eventuallyled to the solving of its structure. Fischer took his own lifeat the end of the World War II after his laboratories hadbeen destroyed in the bombing of Munich.

Figure 17. Hans Fischer

Among Emil Fischers students who made importantcontributions in fields unrelated to his main research inter-ests was Helmuth Scheibler [18821966][133] (Figure 18).After studying in Geneva, Munich and Berlin, he obtainedhis Dr. phil. degree in 1909 for work with Fischer on valinedipeptides and on the Walden inversion,[134] and, as a re-search assistant, he first continued with the investigationsof amino acids. He then turned to the study of thiophenecomponents of ichthyol oil with which he habilitated in1915 at the Technical University of Berlin (Charlottenburg),which was to become his place of work for both, teachingand research for the next 40 years, first as associate andthen as full professor. His main line of research, beginningin about 1925,[135] centered on compounds with divalent

F. W. LichtenthalerMICROREVIEWcarbon, leading to many fundamental contributions whichlaid the basis for carbene chemistry.

Figure 18. Helmuth Scheibler

Among those who worked with Fischer in the years be-fore World War I were four men who continued researchon problems to which they had been introduced by Fischer:G. Zemplen, K. Freudenberg, B. Helferich, and H. O. L.Fischer, the eldest of his three sons.

Geza Zemplen [18831956][136] (Figure 19), is justly con-sidered to be the founder of organic chemistry in Hunga-ry.[136c] He had studied chemistry at the University of Bu-dapest, received his Dr. phil. degree in 1904 for work withKaroly Than on the surface tension of aqueous solutionsand, in 1905 he joined the Mining and Forestry School atSelmeczbanya (Schemnitz, today Slovakia) as an assistant.With a fellowship from the Hungarian Ministry of Agricul-ture he spent nearly three years (19071910) in Fischerslaboratory in Berlin, successfully working on topics of am-ino acid chemistry (synthesis of - and -proline, ornithine,and piperidones[137]) and sugars (derivatization and enzym-atic behavior of cellobiose[138]), as evidenced by eight jointpublications, and by several comprehensive accounts forAbderhaldens Handbuch der biologischen Arbeitsmethoden.After his return to Selmeczbanya, he continued research oncarbohydrates, with which he habilitated in 1912 at the Uni-versity of Budapest. When, in 1913, the first Chair of Or-ganic Chemistry in Hungary was established at the Tech-nical University of Budapest, Emil Fischer played a decisivepart in Zemplens appointment. He was only 29 at the timeand there were several applicants for the post; but the thenrector, G. Rados, sought Fischers advise, and, on a mostfavorable assessment,[139,140] Zemplen was appointed. In theselection of his research topics and particularly in the wayhe carried them out, Zemplen was greatly influenced byEmil Fischer, as he continued research in the field of carbo-hydrates and, over the years interrupted by the destruc-tion of his institute during World War II turned out animpressive series of important papers on the synthesis ofoligosaccharides and of numerous naturally occuring gly-

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cosides. His legacy lives on in his many pupils, some ofwhom achieved particular eminence in Hungary as well asabroad (see Figure 5).

Figure 19. Geza Zemplen

Karl Freudenberg [18861983][141,142] (Figure 20) workedwith Fischer between 1908 and 1914, first as a doctoral stu-dent, receiving his Dr. phil. degree in 1910 for studies onphenolcarboxylic acid derivatives,[143] then as a research as-sistant carrying out the first investigations on depsides andtannins.[144] Strength of purpose and self-confidence wereshown early by the young Freudenberg in that he managedto start work independently while still with Fischer, and,perhaps even more characteristically, it was he who effectedthe disengagement from his illustrious teacher. As a firstindependent research topic he had chosen to study the con-figurational relationships between tartaric, malic, lactic,and glyceric acids[145] by converting levorotatory malic acidin a series of reactions into the equally levorotatory glycericand lactic acids. When, before publication, he presented theresults with apparent success at an institute colloquium, therenowned physicist Madelung overwhelmed him with un-stinted praise saying: Das war eine echte Fischer-Arbeit.Freudenbergs reaction was that of a painful awakening: Ifsomebody had hit me on the head with a truncheon, theeffect would have been the same; what Madelung said wastrue, alarmingly true, and in a flash I realized to what extentI was caught in the world of ideas of my teacher. [141a]

His immediate response was to distance himself from EmilFischer, accepting an assistantship with Harries at the Uni-versity of Kiel only a few days later. There, he was able tocomplete his Habilitation in the autumn of 1914, just beforemilitary service in World War I interrupted all scientific ac-

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWtivities for four years. In 1919 he resumed his position atKiel, and this was followed in rapid succession by pro-fessorships at Munich (1920), Freiburg (1921), Karlsruhe(1922), and finally at Heidelberg (1926) as the successor toCurtius.

Figure 20. Karl Freudenberg

Three major lines of research, clearly emanating fromFreudenbergs time with Emil Fischer, were taken up in theearly 1920s and, growing in scope and intensity, carried onthrough his scientific career which lasted almost 50 years.These investigations were on the absolute configuration ofsterically related compounds culminating in the basic text-book Stereochemie in 1933,[146] further exploration of thechemistry of tannins, and studies on mono- and polysac-charides, particular highlights being the proposition in 1921that cellulose is composed of cellobiose units to the extentof 60%, and, most probably, totally,[147] the proof beingprovided in March 1928,[148] a month before it was alsosubmitted by Haworth.[149] The first proposal of a helicalstructure for starch was to follow in 1939[150] in the contextof clarifying the constitution of the cyclodextrins. Freuden-bergs main occupation in the last four decades of his un-usually long scientific life was concerned with unravellingof the complex framework of lignin tenacious and, forthat time, truly pioneering studies. It bears to his unusual

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vigour and productive capacity that, at the age of 80, henot only conceived a constitutional scheme for the ligninof spruce but also provided the basis for its biochemicalformation in the plant.[151]

After studying at Lausanne and Munich, Burckhardt Hel-ferich [18871982][142,152] (Figure 21), was accepted byEmil Fischer as doctoral student in 1909, received his Dr.phil. degree in 1911 for work on the synthesis of glucos-ides,[153] and continued that research as Privatassistentwhich led to the preparation of the first nucleosides[154] bya method that became known as the Fischer-Helferichprocedure.[155] After serving for four years as an artilleryofficer in World War I, he resumed his position at theChemical Institute in Berlin, started independent researchwhich led to his Habilitation in 1920 and professorships inFrankfurt (1922), Greifswald (1925), and Leipzig (1930). In1945, he was relocated by the American occupying forces,and was at the University of Bonn from 1947 to 1960. Themain lines of research he pursued through all these moveshad originated in Berlin, i.e. extensive studies on the specif-ity of enzymes, especially of sweet-almond emulsin, and sys-tematic investigations into the stereoselective synthesis ofdi- and oligo-saccharides the latter a term proposed byHelferich in 1930.[156] This work also led to the introductionof the highly useful trityl group for blocking primary hy-droxyls in sugars.[157] Notably, his first [153] and last publica-tion on this subject[158] are 63 years apart. A good manyother topics were pursued, extending into non-carbohydrateand even inorganic themes. Altogether 328 publications em-anated from Helferichs laboratory[152b] giving ample evid-ence of the prolific flow of his ideas and his powerful dy-namism that enabled him to realize them. Throughout hislong life, Helferich was nonetheless aware of to whom heowed his success. As he remarked in 1951 upon receivingthe German Chemical Societys Emil Fischer Medal:[159] Ihad the privilege to work for years first as doctoral stu-dent, then as assistant with Emil Fischer, by whom I wasled to whatever I have accomplished.

Figure 21. Burckhardt Helferich

F. W. LichtenthalerMICROREVIEWThe scientific career of Hermann O. L. Fischer

[18881960],[85,142,160] the eldest of Emil Fischers threesons, was to follow an unusually cosmopolitan course. Afterstudying chemistry at the Universities of Berlin and Cam-bridge, England, at the behest of his father, he did his doc-toral work with Ludwig Knorr at the University of Jena,because in another university which the young Fischerwould have preferred, the habits in the chemical institutewere considered to be somewhat too alcoholic.[85] Afterbeing granted the Dr. phil. degree in 1912 for studies on theenol form of -diketones,[84] Hermann Fischer joined hisfathers laboratory to continue research under his guidancefor a two-year period, which generated four joint publica-tions on the synthesis of naturally occurring depsides.[161]

This work was ruthlessly interrupted by the outbreak ofWorld War I in which Hermann served in a military warfareunit. On his return in 1918, he started to redevelop his ca-reer in chemistry, a task that aside the disturbed politicalconditions was made all the more difficult by the devastat-ing loss of his father in July 1919. However, he succeededin gathering together a small research group with which hegradually developed two main lines of research, one com-prising the difficult chemistry of phosphorylated lower-car-bon sugars, the other dealing with cyclic plant acids, suchas quinic and shikimic acid. With these studies he habilit-ated in 1922 and held the position of assistant professor forthe next ten years, the Berlin Institute only returning to itsnormal functioning in about 1924 under the leadership ofWilhelm Schlenk, Emil Fischers successor.

Seeking to escape the tragic events that were to occur inthe later 1930s and which were already taking shape at thebeginning of that decade, Hermann Fischer first moved toSwitzerland where for five years he was associate professorof chemistry at the Pharmaceutical Institute of the Univer-sity of Basle, and in 1937 emigrated to Canada, acceptinga research professorship at the Banting Institute of the Uni-versity of Toronto. The major reasons for this at the timeunusual move were not only the very favorable researchconditions he was offered there, but, in his words,[85] it wastoo clear that war was coming and I did not want my sonsto serve in the army where ideals did not conform withthose of the family; another reason may have been that hiswife was Jewish. He became a Canadian citizen in 1938 bya special act of Parliament. However, in 1953, he adoptedthe American citizenship having joined the newly estab-lished Biochemistry Department of the University of Cali-fornia at Berkeley in 1948.

Hermann Fischers contributions to carbohydrate chem-istry and biochemistry are characterized by their elegance,precision, and biological significance. In 1932 he synthe-sized ,-glyceraldehyde 3-phosphate[162] of which War-burg, Embden, and Meyerhof showed that only the -en-antiomer is fermentable. In a remarkably stereoselective al-dol addition that today would be labeled biomimetic, di-hydroxyacetone and -glyceraldehyde were shown undervery mild basic conditions to give -fructose and -sorbosein high yields.[163] Work on quinic and shikimic acid eventu-ally led to the establishment of their structures and absolute

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configurations during 19321937,[164] yet the real rewardfor this meticulous work was to come some 15 years laterwhen a sample prepared by Fischer enabled B. D. Davis[165]

to identify shikimic acid as a major biosynthetic interme-diate in the formation of aromatic amino acids. Simple pro-cedures for ascending and descending the sugar series weredeveloped, as well as a novel synthesis of 3-amino sugarsby cyclization of sugar dialdehydes with nitromethane.[166]

His synthesis of -erythrose 4-phosphate[167] proved to beof biochemical significance as it soon was shown by D. B.Sprinson to be converted by E. coli, in the presence of phos-phoenolpyruvate, to 5-dehydroshikimic acid.[168] It is a trib-ute to the intelligence, imagination, and assiduousness ofHermann Fischer that despite the delayed start of his aca-demic career, the emotional shock of a war in which helost all his immediate family, his frequent moves with theirattendant adjustments, and the handicap or was it a chal-lenge? of having to live up to the reputation of his illustri-ous father, he produced so many significant and highly ori-ginal works.

The centenary of Emil Fischers birth 9 October 1952 was celebrated at UC Berkeley by the official opening ofthe Biochemistry and Virus Laboratory and the donationby Hermann Fischer of a unique and valuable library ofapproximately 4000 volumes to the University a collec-tion which was started by the father and kept intact by theson throughout his three moves from country to country.Wendell M. Stanley, the eminent virologist,[169] in his capa-city as Chairman of the Department, officially accepted thelibrary and the bronze bust of Emil Fischer (Figure 22),which bears an inscription on the pedestal Emil Fischer,Father of Biochemistry. The library, which still cherishesthis bust, today is named Emil and Hermann Fischer Lib-rary. Another memorable occasion was at the 1952 fallmeeting of the American Chemical Society in Atlantic City,when Hermann Fischer presented Claude S. Hudson[170]

Figure 22. Hermann O. L. Fischer and Wendell M. Stanley[169](right) on 9 October 1952, the 100th birthday of Emil Fischer, atthe dedicatory ceremony donating his fathers personal library tothe Biochemistry and Virus Laboratory of the University of Cali-fornia, Berkeley

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEW

Figure 23. Claude S. Hudson (left) at the 1952 fall meeting of theAmerican Chemical Society in Atlantic City, after being presentedEmil Fischers golden watch and chain by Hermann O. L. Fischer

with his fathers gold pocket watch and chain (see Figure23 and Figure 2, top right) recognizing him as a true suc-cessor to Emil Fischer. Hudson used to wear it only onstate occasions.

The profound influence of Fischers scientific successorswas particularly evident in the 20th century development ofbiochemistry in the United States. The first of the notableAmericans to work in Fischers Berlin Institute albeitonly briefly in the summer of 1902 analyzing gelatine for itsamino acid composition[171] was Phoebus A. T. Levene[18691940][172] (Figure 24), a physician who had emi-grated from Russia to New York. In 1905, he joined thenewly formed Rockefeller Institute for Medical Research,New York, where he remained for the rest of his career

Figure 24. Phoebus A. T. Levene

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working on an extraordinary variety of biochemical prob-lems. His major achievements were the identification of thecarbohydrate components of nucleic acids such as ribose(1909) and deoxyribose (1929).

Similarly brief in his association with Fischer was DonaldD. van Slyke [18831971][173] (Figure 25). He had receivedhis Ph. D. for work with Gomberg at the University ofMichigan in 1907, joined the research group of Levene atthe Rockefeller Institute in 1908, working on peptides frompartial hydrolysates of proteins, and, most notably, develop-ing his classic nitrous acid method for the quantitative de-termination of aliphatic amino nitrogen.[174] In 1911, Le-vene arranged for him a stay with Fischer in Berlin, wherevan Slyke had the privilege of working in Fischers privatelaboratory on reactions of pyrrole carboxylic acid.[175] Afterreturning to the Rockefeller Institute, he spent there thenext 36 years of his distinguished scientific career continu-ing research on proteins, showing that they are completelyhydrolyzed in the mammalian digestive tract and thatamino acids disappear from the blood on passing through thetissues. He also made decisive contributions to clinicalchemistry, e.g. acid-base equilibra and CO2 transport inblood; even in his seventies, he succeeded in isolating a newamino acid from gelatine and showed it to be -hydroxy-lys-ine.

Figure 25. Donald D. van Slyke

A genuine Fischer Schler, who joined the Rockefeller In-stitute, first as assistant to Levene (1908), then as researchassociate with independent status (1912) and a full memberleading the pharmacology laboratory (1923), was Walter A.Jacobs [18831967][176] (Figure 26). A native of New YorkCity, he attended Columbia University to receive an A. B.degree in 1904 and an A. M. in 1905, after which he en-

F. W. LichtenthalerMICROREVIEWrolled at the University of Berlin for study with Fischer toearn his Dr. phil. in 1907 for work on the resolution ofracemic amino acids.[177] During his subsequent affiliationwith the Rockefeller Institute, which lasted nearly 50 years,he made many decisive contributions in various fields oforganic chemistry and biochemistry, e.g. demonstrated thatyeast nucleic acid is composed of ribonucleotides (1910with Levene), discovered Tryparsamide, an arsenical effec-tive in treating African sleeping sickness (1918), establishedthe structure of the cardiac aglycones (19231934), andlater, on extensive studies of alkaloids, first obtained lyser-gic acid as a characteristic aglyconic building block and elu-cidated the intricately complex structures of ergot and vera-trum alkaloids.

Figure 26. Walter A. Jacobs

This illustrious group of former Emil Fischer associatesat New Yorks Rockefeller Institute for Medical Researchwas joined in 1922 by Landsteiner and, in 1933, by MaxBergmann [18861944][178] (Figure 27) who as a Jew hadbeen dismissed from his scientific position in Dresden andsought refuge in the United States. Bergmann had studiedchemistry at the Universities of Munich and Berlin, andreceived his Dr. phil. degree with I. Bloch for work on acylpolysulfides in 1911. He then entered Fischers group, soonbecoming his chief research assistant, during World War Ide facto running the institute via extensive correspondencewith his teacher, who was frequently absent for long periodsto recuperate from various illnesses. His research activitieswith Fischer were highly varied, comprising work on aminoacids,[179] carbohydrates,[180] depsides,[181] and glycer-ides.[182] After Fischers death in 1919, Bergmann automat-ically became his scientific executor, assuming responsibilityfor the completion and publication of unfinished researches,and the editing of his autobiographical memoir[38] and col-lected papers.[26c26f] In 1920, he habilitated at the Univer-sity of Berlin, yet only a year later already was appointedto head the newly established Kaiser-Wilhelm-Institut frLederforschung in Dresden. There he continued his investi-

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gations on carbohydrates and peptides, strongly emphasiz-ing that the latter should conform with the demands of theInstitute, which was concerned with chemical studies ofleather and tanning processes. A series of important contri-butions emanated from the research during this decade: thepreparation of diketopiperazines from serine and cystine,the elaboration of a general method for the acquisition ofdehydro amino acids, the exploitation of azlactones for pep-tide synthesis, and the useful process for racemization ofamino acids with acetic anhydride. In 1932, Bergmann withhis student Zervas developed what was perhaps his greatestcontribution to peptide synthesis, the carbobenzoxymethod. This was immediately adopted as a standard prac-tice by other workers as, unlike Fischers halogenoacyl hal-ide procedure, it allowed the facile synthesis of polypeptidescontaining all amino acids. From 1933, when he left Ger-many and continued his work at the Rockefeller Institute,Bergmanns efforts were largely directed towards the studyof enzyme specificity, first of a dipeptidase, then of papainand various other plant and animal enzymes, as well as to-wards the development of new methods for the amino acidanalysis of proteins. This work, at first, was interrupted byBergmanns untimely death in 1944, but was then continuedby his associates William H. Stein and Stanford Moore,who shared the 1972 Nobel Prize in Chemistry for theirachievements in this field.

Figure 27. Max Bergmann

To these distinguished scientists of the Rockefeller Insti-tute, who have all left their mark on the development of thebiochemical sciences in the United States, must be addedanother former Fischer associate, the Englishman HansThacher Clarke [18871872][183] (Figure 28), a cousin, infact, of B. Helferich. In 1905, Clarke entered UniversityCollege London, obtained a B. Sc. in 1908, and wasawarded a scholarship in 1911 which enabled him to workin Fischers laboratory in Berlin as a research guest for threesemesters. Although working on problems of his own (thesynthesis of alkylthiazines[184]) he had the privilege of being

Emil Fischer, His Personality, His Achievements, and His Scientific Progeny MICROREVIEWvisited by Fischer almost daily for extensive discus-sions.[183a] In 1914, Clarke joined the research staff of theEastman Kodak Co. in Rochester, N. Y., and, in 1928, ac-cepted the challenge to head the Department of BiologicalChemistry at the College of Physicians and Surgeons ofColumbia University where, within a few years, he had as-sembled one of the strongest faculties in biochemical re-search and education in the U.S. This success was the resultof his liberal policy in encouraging his associates to under-take independent research and seeking out talented researchworkers. This attitude opened up the laboratory to studentswho had left Germany due to the prevailing racial policy,such as Konrad Bloch,[185] who worked for his Ph. D. underClarkes guidance. He also attracted a distinguished array ofscientists, such as Erwin Chargaff, Zacharias Dische, KarlMeyer, David Nachmansohn, Rudolf Schoenheimer, andHeinrich Waelsch, who ultimately became members of thefaculty. Due to Clarkes long association with industry, hisoutput of scientific papers was modest. However, he didcontribute over 30 entries to Organic Synthesis, edited twovolumes, and made some important advances in cystinechemistry which were of considerable use in his laboratoryby Williams for elaborating the structural formula of vi-tamin B1.[127]

Figure 28. Hans T. Clarke

As altogether 112 of Fischers doctoral students andpostdoctoral associates decided for research careers in uni-versities and research institutions, not only the twenty men-tioned in the geneological tree of Figure 5 gained later dis-tinction, but many others as well. Ernest Fourneaux[18721949],[186] for example, who divided his postdoctoraleducation in Germany between Curtius (Heidelberg),Fischer (Berlin, 1901[187]), and Willsttter (Munich), laterwas head of the Poulenc research laboratories (19021910)and then, for 33 years, of the Pasteur Institute, became thefounder of French th