ANIMALCULES •

Fame, Failure, and Yellowjack • ! The stories of Hideyo Noguchi and Max Theiler show how even major talents in science can 'flourish or be dissipated in the dogged pursuit of erroneous ideas

Bernard Dixon

century ago, the Japanese bacteriol­ took up in 1922. Once at Harvard, Theiler ogist Hideyo Noguchi became a became friendly with Zinsser and - this being in member of the staff of the Rock­ the midst of Prohibition-was soon exchanging efeller Institute in New York, a post recipes for home brewing. he held until 1928 when he died at And thus to yellow fever. Theiler found him­ the age of 51. It's an appropriate time, then, to self in the midst of a passionate debate about the reflect on the career of this charming, dedicated cause of the condition. Two decades earlier, yet obstinate man and on how it intersected with Walter Reed and James Carroll, working for a that of his contemporary, South Africa-born U.S. Army Commission studying the disease in Max Theiler. Havana, Cuba, had produced evidence that a Theiler achieved international acclaim and a filterable virus was responsible. But this had Nobel prize in 1951 after evolving one of the failed to resolve the issue to everyone's satisfac­ most successful vaccines ever developed, the tion. 17D vaccine against yellow fever. Noguchi, de­ In particular, Hideyo Noguchi, working at spite other substantial attainments, strayed onto the Rockefeller Institute, insisted that the culprit a false trail in pursuit of the organism responsi­ was a spirochete. Andrew Sellards, Theiler's ble for the same disease. He even succumbed to boss, thought it was a bacterium, though not yellow fever himself- committing, some have Noguchi's spirochete. Theiler, taking a stand alleged, a microbiologist's hara-kiri once he sus­ unlikely to endear him to his new chief, argued pected the truth about his failure. that a virus must be responsible. But first Theiler. He was born in 1899 on a He was right. Soon, he had taken a major step farm near Pretoria, the youngest child of veteri­ forward by making the suspect virus grow for nary bacteriologist Arnold Theiler. As a medical the first time in a laboratory animal, by injecting student at St. Thomas's Hospital, London, he it into the brains of mice. Surviving an attack of did a minimal amount of work. Aided by the disease himself, he wrote up his work for monthly checks from his father, he preferred to Science, provoking hostile criticism from micro­ spend his time in art galleries, at the theater, and biologists at Harvard and elsewhere. He showed reading H.G. Wells and Bernard Shaw. that the virus became attenuated for monkeys Later, however, at the London School of Hy­ when grown in mice, and demonstrated that giene and Tropical Medicine, he happened to immune serum neutralized the organism. Then pick up a copy of Infection and Resistance by he was tempted away by a job at twice his American bacteriologist Hans Zinsser. This current salary at the Rockefeller Foundation. fired his enthusiasm for science-a pursuit that Wilbur Sawyer, the tempter, acted with great contrasted sharply with the helpless, hopeless insight, because Theiler's work had poised him pill-giving he had seen at St. Thomas's and' for two major initiatives. The neutralization test which he later called "hogwash." made it possible, through the screening of sera, It was in London too that he met Oscar to mount a worldwide survey of the disease's Teague from Harvard Medical School, who ar­ distribution. This was put in hand at once. ranged an offer of a post there which Theiler Secondly, it seemed likely that an attenuated

208 • ASM News I Volume 70, Number 5, 2004

I ANIMALCULES

strain of the virus could be developed as a vac­ was in fact indistinguishable from Leptospira cine. Three years and many thousands of tissue icterohemorrhagiae, the ~gent of Weil's disease. - cultures later, a flask labeled 17D yielded the But Noguchi stuck to his guns. He continued virus that was to form the famous vaccine. to do so after the Rockefeller Foundation sent a By 1940 field tests were complete, and over team to the tropics and failed to find his spiro­ • the next seven years the Rockefeller Fouljldation chete in yellow fever patients. He even reaf­ manufactured over 28 million doses. A few firmed his view in 1927 after Adrian Stokes and years later, according to Greer Williams (Virus colleagues, working in the Gold Coast (now Hunters, Hutchinson, 1950), the commuter 'Ghana), transmitted the disease to rhesus mon­ who had been known to fellow travelers from keys by using material passed through a bacte­ Hastings-on-Hudson as "the man who lives rial filter. next door to [baseball player] Alvin Dark" be­ Following the earlier report by Reed and Car­ came "the Nobel prize-winner who lives next roll, this was the definitive confirmation that the door to Alvin Dark." actual causative agent was a virus. Soon after­ All of which contrasts starkly with the tragic wards (even before the work was published), story of Hideyo Noguchi. Born of poor, illiterate Stokes contracted the disease and died. parents in northern Japan, his ambition drove The following year, Noguchi left New York him, at the age of 23, to seek out Simon Flexner for Accra in the Gold Coast. By now very de­ at the University of Pennsylvania. Disappointed pressed, he announced: "I will win down there not to be offered a job, he nevertheless found or die." For some months he searched, unsuc­ support in Philadelphia for work on snake ven­ cessfully, for his spirochete in yellow fever vic­ oms. He also made an unusually deep impres­ tims. Then he too died of the disease. sion on colleagues at that time. There's an odd tailpiece to this saga. In 1996 the government of Ghana issued a set of postage "He was sensitive, naive, generous to a fault, stamps to mark the 120th anniversary of Nogu­ save where honors were concerned, a spend­ chi's birth. This prompted Torsten Wiesel, pres­ thrift in time, money and energy, a man of ident of Rockefeller University, to write: "I ap­ extraordinary drive and industry," writes Paul preciate the beautiful stamps celebrating the F. Clark in Pioneer Microbiologists of America 120th anniversary celebration of the birth of Dr. (University of Wisconsin Press, 1961). "We ap­ H. Noguchi issued by the Ghana government. preciated his childlike simplicity, directness, and Perhaps you could inform me as to why the the fireball intensity of his purpose, and forgave Ghana government decided to commemorate his foibles and weaknesses." Dr. Noguchi." Before Noguchi became interested in yellow As reported by S. S. Koide of the Population fever, he conducted important studies in several Council in New York (j. Med.Biography 8:97, disparate fields. He provided the first detailed 2000), the decision had been taken "because of description of hemolysis triggered by snake ven­ Noguchi's undaunted devotion and endeavour oms, and of the damage caused to the endothe­ in identifying the causative agent of yellow fever lium of blood vessels, leading to hemorrhage and in developing a vaccine against this disease and edema. His mark presaged the development in Accra during 1927-8. His presence there had in goats of an antidote to rattlesnake venom. a profound impact on the livelihood of the peo­ And his meticulous studies resolved uncertain­ ple in and about the Gold Coast. He exuded ties about the role of Bartonella bacilliformis in hope that inspired confidence that this scourge causing both Oroya fever and verruga peruana. could be exterminated by executing a frontal However, it was yellow fever that proved to attack on this microscopic enemy in a dramatic, be Noguchi's downfall. The problem arose from 'blood and guts' charge." his absorption, some might say obsession, with One can only speculate as to whether Nogu­ spirochetes, which he sought in a wide variety of chi would have ,been pleased to receive this different infections and tissues. Working at the enthusiastic though largely unwarranted trib­ same time as Theiler, he isolated one such or­ ute. He might be happier to know that even ganism which he believed to be the cause of today his name is remembered in the binomial yellow fever and named it Leptospira icteroides. attached to one of his beloved spirochetes, Lep­ However, Theiler and Sellards showed that this tospira noguchii.

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