NOGUCHI, (SEISAKU) HIDEYO

(b. Sanjogata, Okinashima-mura, Fukushima, Honshu, Japan, 24 November 1876; d. Accra, Gold Coast, 21 May 1928)

microbiology.

Despite humble origins and a physical handicap, Noguchi attained extraordinary fame during his lifetime. He discovered Treponema pallidum in the brain of general paralytics, and he proved that either Oroya fever or verruga peruana might be produced by Bartonella bacilliformis. But his technique and conculations were often faulty, and his work on Leptospira icteroides as the causal agent of yellow fever was gravely misleading.

Noguchi was the second child and only son of Sayosuke, a thriftless peasant, and his illiterate but industrious wife, Shika; he was given the name Seisaku. As an infant he was burned by an indoor brazier, and his left hand was seriously injured. After rapid elementary schooling, he attended secondary school at Inawashiro, a distance of three miles from his home, and graduated with honors at age seventeen. While working as dispenser to a local surgeon (who restored partial function to his crippled hand) and as janitor at a dental college, he studied medicine from borrowed books. Helped financially by friends, he briefly attended a proprietary medical school in Tokyo, receiving his practitioner’s diploma in 1897.

Various temporary appointments then followed, including an assistantship at S. Kitasato’s Institute for Infectious Diseases, where advancement was slow. Noguchi then replaced the name Seisaku by Hideyo (“to excel in the world”). When Simon Flexner visited the Institute in 1899, leading a medical commission from the Johns Hopkins University, Noguchi expressed a desire to study pathology and bacteriology in the United States. Flexner cautiously endorsed the wish. In December 1900, having borrowed passage money, Noguchi arrived unannounced and penniless at the University of Pennsylvania, where Flexner had become professor of pathology. With Weir Mitchell’s modest support, Noguchi began snake venom investigations under Flexner’s tutelage.

Noguchi amassed data for a dozen papers, and grants were forthcoming. In 1903 the Carnegie Institution appointed Noguchi research assistant and awarded him a one-year fellowship at the Statens Seruminstitut, Copenhagen. He was befriended by Thorvald Madsen, who stressed quantitative accuracy and physicochemical concepts in their immunologic studies, mainly of venous and potent antivenins. Late in 1904 Noguchi began an assistantship at the Rockefeller Institute for Medical Research, inaugurated under Flexner’s direction. He and Flexner were the first scientists in America to confirm F. Schaudinn’s discovery of,Spirochaeta pallida(1905). Following A. Wassermann’s publication of his complement fixation test (1906). Noguchi became preoccupied with problem of syphilis and produced twenty papers and a book on serodiagnostic methods. Between 1909 and 1913 he cultured Sp. pallida and various other spirochetes in artificial media, described specific cutaneous reactions in latent and tertiary syphilitics after intradermal injection of emulsified spirochetes (“luetin”), and detected Sp. pallida in the brain of paretics—the sole enduring accomplishment of this prolific period. He also reported on cultivable bodies as probable causal agents of poliomyelitis, rabies, and trachoma. Late in 1913 his lecture-demonstrations were received triumphantly in European medical centers. His promotion to membership in the Institute ensued from these researches.

In 1915 Noguchi visited his ailing mother in Japan and received the Order of the Rising Sun and an Imperial Prize. He also learned of Spirochaeta icterhaemorrhagiae, recently identified by R. Inada and Y. Ido as the causative agent of hemorrhagic jaundice (Weil’s disease). Noguchi made extensive studies of this microorganism, whose generic name he revised to Leptospira, Soon after reaching Guayaquil in 1918 with the Rockefeller Foundation yellow fever commission to Ecuador, he isolated an organism resembling Leptospira ictrohaemorrhagiae from several allegedly classic cases of yellow fever. Convalescent patients’ serums showed positive “ Pfeiffer reactions “ (specific bacteriolysis) with this organism, which he named Leptospira icteroides; outbreaks of the disease in Yucatan, Peru, and Brazil yielded similar evidence. Guinea pigs injected with L. icteroides as the causative agent of yellow fever appeared between 1919 and 1922, in the Journal of Experimental Medicine, then under Flexner’s editorship. Yellow fever prophylactic vaccine and therapeutic antiserum were prepared from this organism and distributed experimentally by the Rockefeller Institute until 1926. Noguchi’s inconclusive experimental data had been superimposed on the fallacious presumptions that leptospiral jaundice and yellow fever were distingsuishable by regional physicians and were caused by kindred agents. Criticism was silenced initially by overenthusiasm, but in 1924, at a Jamaican conference on tropical medicine, the leptospiral theory was disputed on various grounds. By then, yellow fever had practically vanished from the Western Hemisphere, and further tests therefore awaited transfer of the campaign to West Africa.

Noguchi had meanwhile solved the long-standing enigma concerning the relationship between Oroya fever (Carrión’s disease) and verruga peruana. Using his special Leptospira medium, he isolated Bartonella bacilliformis (previously uncultivated) from an Oroya fever patient’s blood, and also from verruga nodules. This microorganism, administered intravenously to macaques, provoked an acute febrile anemia, whereas intradermal inoculations caused local verruga formation. Thus the etiologic unity of these diseases was established. He simultaneously resumed enquiries into trachoma among Arizona Indians and isolated Bacterium granulosis, which induced progressive granular conjunctivitis when injected into the conjunctive of monkeys and chimpanzees. Norwithstanding his stimulation monograph on trachoma (1928), this bacillus gained little credence.

In 1927 the leptospiral theory was finally discredited by careful reports that L. icteroides and by investigations sponsored by the Rockefeller Foundation International Health Board in Nigeria since late 1925. After negative bacteriologic findings in sixty-seven typicals cases, a filterble virus was implicated, undetected by guinea pigs, but producing characteristic fatal lesions in rhesus monkeys. Convalescent human serums protected such animals, but L. icteroides vaccine and antiserum did not. In September 1927, before these result were published, the senior author, Adrian Stokes, died from yellow fever. Noguchi sailed for Africa in October. He established himself at Accra, Gold Coast, in the Medical research institute; the director, W. A. Young, collaborated closed with Noguchi. By frenzied. often solitary work, day and night, Noguchi apparently confirmed the viral findings, but also isolated a banal bacillus that he considered significant. When about to depart for New York, after six unhappy months, he fell ill and in nine days died of yellow fever. One week later, the same fate befell Young. A marble memorial to their joint research was erected in the Institute’s compound at Accra. Noguchi’s tomb, surmounted by natural rack, is in Woodlawn Cemetery, New York.

Speculation centered upon the manner of Noguchi’s fatal infection. To some, increasing despondency and ill health suggested that he courted infection, fulfilling a youthful motto, “Success or suicide”, others, particularly in Japan, viewed his death as martyrdom, worthy of veneration. Noguchi’s quick perceptivity and remarkable energy often permitted him to correct or amplify the more original discoveries of others. Unfortunately, he applied bacteriologic techniques to many viral diseases. In the laboratory he was deft and ingenious, but disorderly and extravagant; at Accra, for example, he accumulated over 500 monkeys. These qualities were magnified by his propensity for working alone upon multiple projects. His small stature, fine head, and oriental manners could be very appealing, despite his frequent unpredictability and moodiness. An unannounced, childless marriage to Mary Dardis in 1912 moderated a tempestuous life.

Noguchi’s spoken English was difficult to follow, and his writings needed editing; but he understood many languages. Various universities conferred honorary doctorates, and several countries granted honors and decorations. He was awarded the John Scott Medal (1920) and the Kober Medal (1925). Noguchi’s tragedy lay not in lack of recognition, but arose from insatiable ambition, reckless industry, and shrewd intelligence so overlaid with disarming modesty and charm that mentors and benefactors in Japan and America minimized his faults and overestimated his capabilities. He owed an incalculable debt to the Rockefeller Institute for Medical Research, which fostered his activities for a quarter-century. In its library stands a striking bronze bust of Noguchi done in his last year of life.

BIBLIOGRAPHY

I. Original Works. A list of Noguchi’s publications, comprising 186 titles, was prepared and bound with 81 collected reprints by the Rockefeller Institute for Medical Research (now the Rockefeller University). In 1935 some 20 sets of this bibliography were distributed to selected libraries in the United States, Japan, and Europe. The list has minor inaccuracies and omissions. Most of his writings are in English, but a few appear only in German, French, or Spanish. Many articles had multiple publication, sometimes in two or more foreign-language journals.

Noguchi’s books are Snake Venoms (Washington, 1909); Serum Diagnosis of Syphilis and the Butyric Acid Test for Syphilis (Philadelphia, 1910; 2nd ed., 1911; 3rd ed., 1912); and Laboratory Diagnosis of Syphilis (New York, 1923). He also contributed chapters to various texts, of which the more noteworthy are “Snake Venoms.” in W. Osler and T. McCrae, eds., System of Medicine, I (London, 1907), 247–265; “Serodiagnostic de la syphilis,” in A. Gilbert and M. Weinberg, eds., Traite du sang (paris,1921); “Yellow Fever,"” in R. L. F. Cecil, ed., Textbook of Medicine (Philadelphia, 1927); and “The Spirochetes,” in E. O. Jordan and I. S. Falk, eds., The Newer Knowledge of Bacteriology and Immunology (Chicago, 1928), 452–497.

His early contributions to the knowledge of snake venoms and antivenins and of hemolysins, include “Snake Venom in Relation to Haemolysis, Bacteriolysis, and Toxicity,” in Journal of Experimental Medicine, 6 (1902), 277–301, and “On the Plurality of Cytolysins in Snake Venom,” in Journal of Pathology and Bacteriology, 10 (1905), 111–124, both written with S. Flexner; “The Photodynamic Action of Eosin and Erythrosin Upon Snake Venom,” in Journal of Experimental Medicine, 8 (1906), 252–267; “The Influence of Temperature Upon the Rate of Reaction (Haemolysis, Agglutination, Precipitation),” ibid., 337–364, written with T. Madsen and L. Walbum; and “Toxins and Antitoxins_Snake Venoms and Antivenins,” ibid., 9 (1907), 18–50, written with T. Madsen

Among his reports on the serodiagnosis of syphilis are “The Relation of Protein, Lipoids and Salts to the Wassermann Reaction,” ibid., 11 (1909), 84–99; “A New and Simple Method for the Serum Diagnosis of Syphilis,” ibid., 392–401; “The Present Status Serodiagnosis of Syphlisis,” in Interstate Medical journal, 18(1911), 11–25; “Biochemical Studies on So-called Syphilis Antigen,” in Journal of Experimental Medicine, 13 (1911), 43–68, and “The Comparative Merits of Various Complements and Amboceptors in the Serum Diagnosis Syphilis,” ibid., 78–91, both written with J. Bronfenbrenner; “A Cutaneous Reaction in Syphilis,” ibid., 14 (1911), 557–568; “Experimental Research in Syphilis, With Especial Reference to Spirochaeta pallida (Treponema pallidum),” in Journal of the American Medical Association, 58 (1912), 1163–1172, the FengerSenn Memorial Address; “A Homohemolyyic Syatem for the Serum Diagnosis of Syphilis,” in Journal of Experimental Medicine, 28 (1918), 43–67.

His wide-ranging studies of spirochetes include “On the Occurrence of Spirochatea pallida, Schaudinn, in Syphilis,”in Medical News, 86 (1905), 1145, written with S. Flexner; “A Method for the pure Cultivation of Pathogenic Treponema pallidum (Spirochaet duttoni,Spirochaeta Kochi, Spirochaeta novyi,” ibid., 16 (1921), 199–210; “A Demonstration of Treponema pallidum in the Brain Cases of General Paralysis,” ibid.,17 (1913), 232–238, written with J. W. Moore; “Spirochates,” in Journal of laboratoryand Clinical Medicine, 2 (1917),365–400, 472–499, the Harvey lecture; “Spirochaeta icterohaemorrhagiae in American Wild Rats and Its Relation to the Japanese and European Strains,” in Journal of Experimental Medivine, 25 (1917), 755–763; “Morphological Characteristics and Nomenclature of Leptospira (Spirochaeta) icterohaemorrhagiae (Inada and Ido),” ibid., 27 (1918), 575–592; and “The survival of Leptospira (Spirochaeta) icterohaemorrhagiae in Nature; Observations Concerning Microchemical Reactions and Intermediary Hosts,” ibid., 609–625.

Noguchi’s fallacious claims respecting yellow fever involve over 30 papers. The laboratory data, embodied mainly in a series of 18 reports in the Journal of Experimental Medicine, include “Etiology of Yellow Fever. I. Symptomatology and Pathological Findings of the Yellow Fever Prevalent in Guayaquil,” in Journal of Experimental Medicine, 29 (1919), 547–564; “II. Transmission Experiments on Yellow Fever,” ibid., 565–584; “III. Symptomatology and Pathological Findings in Animals Experimentally Infected,” ibid., 585–596;” VI. Cultivation, Morphology, Virulence, and Biological Properties of Leptospira icteroides,” ibid., 30 (1919), 13–29; “VII. Demonstration of Leptospira icteroides in the Blood, Tissues, and Urine of Yellow Fever Patients and of Animals Experimentally Infected With the Organism,” ibid., 87–93; “IX. Mosquitoes in Relation to Yellow Fever,” ibid., 401–410; and “X. Comparative Immunological Studies in Leptospira icteroides and Leptospira icterohaemorrhagiae,” ibid., 31 (1920), 135–158. Among four papers written with I. J. Kligler are “Immunological Studies With a Strain of Leptospira on Yellow Fever in Northern Peru,” ibid., 33 (1921), 239–252.

Other key publications, ibid., Prophylactic Inoculation Against Yellow Fever,” in Journal of the American Medical Association, 76 (1921), 96–99, written with W. Pareja; “Prophylaxis and Serum Therapy of Yellow Fever,” ibid., 77 (1921), 181–185; Experimental Studies of Yellow Fever in Northern Brazil, Monograph no. 20, Rockefeller Institute for Medical Research (New York, 1924), 131–138; and “Yellow Fever Research, 1918–1924: A Summary,” in Journal of Tropical Medicine and Hygiene, 28 (1925), 185–193.

Noguchi’s earliest searches for the causal agent of trachoma appeared as “The Relationship of the So-called Trachoma Bodies to Conjunctival Affections,” in Archives of Ophthalmology, 40 (1911), 1–9, and culminated in his monography “The Etiology of Trachoma,”, in Journal of Experimental Medicine, 48 (1928), supp. no. 2. Misleading reports on the causal agents of rabies and poliomyelitis are “Contribution to the Cultivation of Parasite of Rabies,“ in Journal of Experimental Medicine, 18 (1913), 314-316; “Experiments on the Cultivation of the Microorganism Causing Epidemic Poliomyelitis,” ibid., 461–485, written with S. Flexner; and “Concerning Survival and Virulence of the Microorganism Cultivated From Poliomyelitis Tissues,” ibid., 21 (1915, 91–102, written with S. Flexner and H. L. Amoss.

Characteristic papers on miscellaneous researches include “Pure Cultivation in Vivo of Vaccine Virus Free From Bacteria,”ibid.,539–570; “Bacteriological and Clinical Studies of an Epidemic of Koch-Weeks Bacillus Conjunctivitis Associated With Cell Inclusion Conjunctivitis,” ibid., 22 (1915), 304–318, written with M. Cohen; “Immunity Studies of Rocky Mountain Spotted Fever. II. Prophylactic Inoculation in Animals” ibid., 38 (1923), 605–626; “The Isolation and Maintenance of Leishmania on the Medium Employed for the Cultivation of Organisms of the Leptospira Group of Spirochetes,” in American Journal of Tropical Medicine, 5 (1925), 63–69, written with A. Lindenberg; and “Comparative Studies of Herpetomonads and Leishmanias. I. Cultivation of Herpetomonads From Insects and Plants,” in Journal of Experimental Medicine, 44 (1926), 307–325, written with E. B. Tilden.

Noguchi’s last series of publications, on the causal agent of Oroya fever and verruga peruana, comprises 17 reports in the Journal of Experimental Medicine, of which three appeared posthumously in 1929. The more important are “Etiology of Oroya Fever. I. Cultivation of Bartonella bacilliformis,” ibid., 43 (1926), 851–864, written with T. S. Battistini; “III. The Behaviour of Bartonella moniliformis in Macacus rhesus,” ibid., 43 (1926), 697–713; “The Etiology of Verruga Peruana,” ibid., 45 (1927), 175–189; “VIII. Experiments on Cross-Immunity Between Oroya Fever and Verruga Peruana,” ibid., 781–786; and “XIV. The Insect Vectors of Carriòn’s Disease,” ibid., 49 (1929), 993–1008, written with R. C. Shannon et al.

Correspondence with Flexner and others is in the Simon Flexner Papers at the American Philosophical Society Library, Philadelphia. Relevant material is also among the Philip S. Hench Collection, Walter Reed Yellow Fever Archive, at the Alderman Library, University of Virginia.

II. Secondary Literature. Memorial addresses delivered at the New York Academy of Medicine on 20 December 1928 are T. Smith, “Hideyo Noguchi, 1876–1928,” in Bulletin of the New York Academy of Medicine, 2nd ser., 5 (1929), 877–884; and W. Welch, ibid., 884–886. The chief obituary is S. Flexner, “Hideyo Noguchi. A Biographical Sketch,” in Science, 69 (1929), 653–660, repr. with portrait in Report of the Smithsonian Institution (1929), pp. 595–608. G. Eckstein, Noguchi (New York-London, 1931), a vivid but awkward biography, lacks an index and authenticating details.

Other reference to Noguchi’s life and work are S. Benison, Tom Rivers. Reflections on a Life in Medicine and Science (Cambridge, Mass., 1967), pp. 93–98; A. R. Burr, Weir Mitchell. His Life and Letters (New York, 1929), pp. 293–296; P. F. Clark, “Hideyo Noguchi, 1876–1928,” in Bulletin of the History of Medicine, 33 (1959), 1–20, with portrait; H. Hanson, The Pied Piper of Peru (Jacksonville, Fla., 1961), pp. 83–85; P. de Kreif, The Sweeping Wind (New York, 1962), pp. 17–18; K. Morishita, “Dr. Noguchi’s Last Photo,” in Tokyo-tji-shinski, no. 3143 (1939), 1920–1921, in Japanese; W. A. Sawyer, “A History of the Activities of the Rockefeller Foundation in the Investigation and Control of Yellow Fever,” in American Journal of Tropical Medicine, 17 (1937), 35–50; M. G. Schultz, “A History of Bartonellosis (Carriòn’s disease),” in American Journal of Tropical Medicine and Hygiene, 17 (1968), 503–515; A. Takahashi, ed., Hideyo Noguchi, November 9, 1876-May 21, 1928 (Tokyo,1961), a booklet published by the Doctor Noguchi Memorial Association; and G. Williams, The Plague Killers (New York, 1969), pp. 215–249.

Crucial reports that finally discredited L. icteroides include A. Agramonte, “Some Observations Upon Yellow Fever Prophylaxis,” in Proceedings of the International Conference on Health Problems in Tropical America, Held at Kington, Jamaica, July 22-August 1, 1924 (Boston, 1924), 201–227; W. Schuffner and A. Mochtar, “Gelbfieber und Weilsche Krankheit,” in Archiv fur Schiffs- u. Tropen-Hygiene, 31 (1927), 149–165; A. W. Sellards, “The Pfeiffer Reaction With Leptospira in Yellow Fever,” in American Journal of Tropical Medicine, 7 (1927), 71–95; A. Stokes et al., “Experimental Transmission of Yellow Fever to Laboratory Animals,” ibid., 8 (1928), 103–164; and M. Theiler and A.W. Sellards, “The Immunological Relationship of Yellow Fever as it Occurs in West Africa and in South America,” in Annals of Tropical Medicine and Parasitology, 22 (1928), 449–460.

Claude E. Dolman