Hideyo Noguchi

Hideyo Noguchi
野口 英世
Born	(1876-11-09)November 9, 1876 Inawashiro, Fukushima, Japan
Died	May 21, 1928(1928-05-21) (aged 51) Accra, Gold Coast
Resting place	Woodlawn Cemetery, New York City, US
Known for	Syphilis Treponema pallidum, Neurosyphilis
Spouse	Mary Loretta Dardis (m. 1912)
Awards	Imperial Prize of the Japan Academy, Order of the Rising Sun, Kober Medal, Order of Dannebrog, Legion of Honour
Scientific career
Fields	Bacteriology, Serology, Immunology
Institutions	Rockefeller Institute for Medical Research, University of Pennsylvania
Japanese name
Kanji	野口 英世
Hiragana	のぐち ひでよ
Transcriptions Romanization Noguchi Hideyo

Hideyo Noguchi (野口 英世, Noguchi Hideyo, November 9, 1876 – May 21, 1928), also known as Seisaku Noguchi (野口 清作, Noguchi Seisaku), was a prominent Japanese bacteriologist at the Rockefeller Institute known for his work on syphilis, yellow fever, antivenom, and Rocky Mountain spotted fever and contributing to the long term understanding of neurosyphilis.^[1]

Before the Rockefeller Institute, his research at the University of Pennsylvania into blood serum and immunity helped lay the foundation for the fields of immunology and serology.^[2][3] Noguchi pioneered the research for antivenoms, producing one of the earliest serums to treat North American rattlesnakes bites.^[4][5] Lastly, he developed the first serum to treat Rocky Mountain spotted fever, a notoriously lethal disease before treatment was discovered.^[6]

During his career, Noguchi discovered Treponema pallidum in the brain and spinal cord tissue of a patient suffering from neurosyphilis, establishing the conclusive link between the mental and physical disease for the first time. John C. Whiteborn considered the discovery an outstanding psychiatric achievement.^[7] Furthermore, Noguchi wrote the popular manuscripts Serum Diagnosis of Syphilis in 1913 and the revision Laboratory Diagnosis of Syphilis in 1922 which aided in the diagnosis and treatment of the disease.^[8][9]

Alongside Kitasato and Shiga, Noguchi was one of the first Japanese bacteriologists to gain international recognition for his scientific contribution, in particular, in the west.^[10] He published over 200 papers and gave lecture tours throughout Europe and North America during his lifetime.^[11] His discoveries were featured regularly in newspapers and he would be nominated several times for a Nobel prize in medicine between 1913 and 1927.^[12][2]

Posthumously, his work on yellow fever, which he mistakenly identified as a bacteria, Leptospira icterohemorrhagiae, was proven wrong as it was a virus. His claims on discovering the causative organisms of rabies, poliomyelitis, and trachoma have not been reproduced along with his pure culture of syphilis. Eventually, Noguchi died of yellow fever in search for the cause of the disease during a trip to Africa.^[13][14]

Hideyo Noguchi, whose childhood name was Seisaku Noguchi,^[15] was born to a family of farmers in Inawashiro, Fukushima prefecture in 1876.^[15] His mother Shika worked in the rice fields, providing for her family and worked to restore her family's honor it once had in the village in the days of her great grandfather and maintain the family farm.^[16][17]

When he was two years old, he fell into an irori, a traditional Japanese sunken fireplace. His elderly grandmother with poor eyesight and deaf along with his four year old sister, Inu, were left watching him.^[16]

His mother heard his scream in the fields.^[16] Noguchi suffered severe burns and an infection developed on his left hand. There was no doctor in the small village. His left hand was useless as the joints of the fingers were gone, and the remaining joints had adhered to each other to form a solid clump. His thumb was drawn down to the wrist and had become attached to it.^[17] While her son could no longer become a farmer, as she hoped. Shika vowed to give her son an education.^[16]

In 1883, Noguchi entered Mitsuwa elementary school. Fifteen years after the accident due to generous contributions from his teacher elementary teacher Kobayashi and friends, Noguchi received surgery for his left hand. He recovered 70% functionality. As shown, Noguchi was given support from the people around him over the course of his life.^[16]

Noguchi decided to become a doctor after his surgery.^[16] In 1893, sixteen year old Noguchi apprenticed at Dr. Kanae Watanabe (渡部 鼎, Watanabe Kanae), the same doctor who had performed the surgery, at his clinic in Aizuwakamatsu.^[16]

In 1872, Japan introduced medical examination for doctors to modernized its medical system during the Meji Restoration.^[16] Except graduates of the exclusive and elite Imperial University, founded in 1877, in Tokyo were exempt from the examination.^[16] Noguchi unable to get into the Imperial University because of his peasant background.^[16] In 1896, he left for Tokyo to receive formal training and prepare for his examination.^[16] After one month, he passed his written portion, and in 1897, he passed the clinical examinations at twenty years old.^[16]

Dr. Watanabe introduced Noguchi to Chiwaki Morinosuke founder of the Takayama Dental College (precursor to the Tokyo Dental College) who took him in as an apprentice. Both Noguchi and Morinosuke became close friend. Noguchi showed signs of great talent. He had three main benefactors, Sakae Kobayashi, his elementary school teacher and father figure,^[18] Kanae Watanabe, the doctor who performed surgery on his hand,^[19] and Morinosuke Chiwaki, who later aided in funding his travel to the United States.^[20]

Eventually, Noguchi worked at the Kitasato Research. Although, he was one of the only doctor to have not graduated from the Imperial University, making him an outsider.^[16]

In 1898, Noguchi changed his first name to Hideyo after reading a novel by Japanese author Tsubouchi Shōyō about a college student whose character had the same name as him. The character in the story, Seisaku, was an intelligent medical student like Noguchi but became lazy and ruined his life.^[21]

In 1899, Noguchi met Simon Flexner during his internship at the Kitasato Institute.^[22] Simon Flexner was visiting Japan to see research from Japanese scientists.^[23] Noguchi was his translator, being one of a few people who spoke English and Japanese, at the Kitasato Institute. Noguchi expressed his desire to work in the United States to Flexner, and Flexner gave polite words encouragement.^[22]

In 1900, Noguchi travelled to the United States on the America Maru. ^[24] Partly, he was motivated by difficulties in obtaining a medical position in Japan as it required expensive schooling.^[20] Noguchi experienced discrimination as employers were concerned his hand deformity would discourage patients.^[20] He felt moving to the United States would find him more success.^[20]

On December 30, 1900, Noguchi arrived in Philadelphia.^[25] He surprised Simon Flexner at the University of Pennsylvania. In spite of their brief correspondence, Noguchi requested a job.^[3] Flexner said the university had no funds. Although, he had been wanting an opportunity to hire an assistant to investigate snake venoms.^[25] Later in Flexner's diary, it can be seen he recognized his courage and persistence for traveling so far from his home country.^[26] The day after he arrived, Flexner asked, "Have you ever studied snake venom?"^[3] Noguchi, not having much experience, but an abundance of determination, said, "Yes, sir, I do know a little about it. I'd like the chance to learn more."^[3]

On January 4, 1901, Noguchi started his research position, earning eight dollars a month coming out of Flexner's pocket.^[3][2] Flexner left for San Francisco to investigate an outbreak of the plague, leaving Noguchi for three months under the guidance of Dr. Silas Weir Mitchell.^[27][28] Despite his lack of knowledge, Flexner returned to find he had written a 250 pages on snake venom.^[28] Flexner was impressed.^[28] In addition, Mitchell and Noguchi wrote a joint research paper, which was his first official publication.^[28] Both presented their scientific findings before the National Academy of Science in Philadelphia, one of the greatest honors an American scientist could have at the time.^[29] Dr. Mitchell spoke during the presentation but Noguchi handled the specimens.^[29]

Dr. Mitchell said after their research concluded...

"It is thanks to the great efforts of this young man that I have been able to bring my thirty years of research to their final conclusion."^[30]

Although, Dr. Mitchell was concerned about his acceptance into larger Western society. ^[28] He recommended him for the Carnegie Fellowship. Officially Noguchi became a researcher and received funding from the Carnegie Institute and National Academy of Science.^[30] Paul Ehrlich wrote to congratulate him.^[31] On July 9, 1907, the University of Pennsylvania awarded Hideyo Noguchi an honorary degree.^[30] On July 19, 1907, he wrote to about the accomplishment,

"Everything is beautiful when it is still in a dream state, but when it becomes a reality it is no longer interesting to me... When one wish comes true, another is born... Now I intend to request a medical degree from the Japanese government."^[32]

Between 1905 and 1908, Noguchi produced 28 papers and reports on his work with snake venoms and the routine observations of immunologic relationships, as well as tetanus.^[33] In 1907, he wrote the chapter on venoms in William Osler and Thomas McCraes Modern Medicine.^[33][34] Previously, French scientist Albert Calmette was the first to produce an antitoxin for venomous snake bites in 1895.^[35] Mitchell had made attempts to produce a serum for rattlesnakes, but was unsuccessful and encouraged his protege.^[4] During which, Noguchi received an invitation to research at the Statens Serum Institute in Copenhagen.^[23] He wrote several papers with fellow bacteriologist, Thorvald Madsen.^[23] Noguchi brought a hundred grams of dried rattlesnake venom to Copenhagen.^[4] Together Noguchi and Madsen produced one of the first antiserums to treat North American rattlesnake bites in 1903.^[4] He was the first to propose the mass production of antivenom in the USA, but not having been realized until Afrânio do Amaral from the Butantan Institute and his research contributed to the development of the first North American rattlesnake antivenom in 1927.^[5][36]

In 1909, Noguchi released a comprehensive monograph on snake venom, Snake Venoms: An Investigation of Venomous Snakes with Special Reference to the Phenomena of Their Venoms.^[23] The publication contained drawings and several photographs of specimens.^[37] In the preface, it stated,

“No single work in the English language exists at this time which treats of the facts of zoological, anatomical, physiological, and pathological features of venomous snakes, with particular reference to the properties of their venoms."^[37]

In 1904, Noguchi returned from the Staten's Institute. He was promised a position at the Rockefeller Institute after Simon Flexner approached him.^[38] There are six members of the new institute.^[39] Noguchi moved to an apartment on Lexington Avenue in New York City. His Japanese friend from the University of Pennsylvania introduced him to Norio Araki, who rented a room in Hideyo Noguchi‘s apartment.^[40] Noguchi and Araki lived together for three years.^[40] He offered to write papers for Araki in English as soon as he gave results. In this period of his career, a fellow research assistant was Frenchman Alexis Carrel, who would go on to win a Nobel Prize in 1912.^[41] When the Rockefeller Hospital opened in 1910, Simon Flexner selected syphilis as one of the top focuses for research. Between 1913 to 1915 held some of Hideyo Noguchi's most notable long lasting discoveries.^[2]

In 1905, Treponema pallidum was first identified as the cause of syphilis by Fritz Schaudinn and Erich Hoffmann.^[22] In 1906, he was the first person in the United States to confirm the spirochete sixty days after its discovery.^[22]

Through the recent breakthroughs, the Wasserman test was announced for diagnosing syphilis in 1906. Wasserman utilized serum reactions, which Noguchi had become familiar with in his studies of snake venom, and he understood the importance and he started working on refining it. His first paper on the subject appeared in 1909. The same year he published another twelve papers in the field.^[33]

Noguchi needed vast amounts of blood samples for his studies. He used his own and asked for some from his roommate Araki begrudgingly.^[42]

Noguchi pioneered the butyric acid test, another method for diagnosing syphilis using fluid from the spinal column.^[43] One doctor reported finding it more sensitive than the Wassermann test for spinal fluid, stating, “Noguchi had prepared for us all the antigen and ambocepter tests that we used. He also spent about two weeks at our laboratory and helped us materially by making many of the tests."^[44]

In 1910, Noguchi published his manuscript, Serum Diagnosis of Syphilis, his most popular publication, assisting doctors and physicians in the diagnosis and treatment of syphilis.^[8]

Dr. Flexner told him to focus his efforts on obtaining a pure culture of the spirochete.^[45] Flexner wrote in his diary, “Once he was started on a problem he would pursue it to the bitter end." Noguchi set up hundreds of tubes for his cultures and used thousands of microscopic slides in his lab.^[46]

In February 1911, Noguchi believed that he had grown a pure culture and wrote to his childhood mentor Kobayashi, “I feel as if I am dancing in heaven." He thought it might eradicate of syphilis.^[46] Although few were able to reproduce his results and his pure culture was considered unreproducible.^[13][47] In 1934, Hans Zinsser, a personal friend of Noguchi, reluctantly said it had not been successful. It was prone to contamination.^[13] Over the next century, bacteriologists and researchers continued struggled to produce a stable culture until 2017.^[48]

Wards Island State Hospital, located on an island in the East River, held the New York State Pathologic Institute and was located opposite of the Rockefeller Institute. Staff members at the Rockefeller Institute, Phoebus Levene and James B. Murphy worked at the Pathologic Institute and were well aware of the problems of patients suffering from paresis. Noguchi began collecting samples from spinal cords and brains of patients that died from tabes dorsalis or of paresis to determine its relationship to syphilis.^[44]

In 1912, Noguchi had collected a total of 200 brains and 12 spinal cords samples from post-mortem patients.^[49] In collboration with J. W. Moore, a psychiatrist at Wards Island, Noguchi discovered the presence of Treponema pallidum in the spinal cord of a patient with tabes dorsalis and paresis. His discovery proved the homogeneity of a mental and physical disease through demonstrating that an organic agent could cause psychosis.^[7][49] His friend and neighbor, Ichiro Hori, reported he bursted into his apartment in the middle of the night, dancing and wearing nothing but his underwear, shouting, “I found it! I found it!"^[44]

With this discovery, Noguchi's influence went beyond bacteriology. John C. Whiteborn wrote about the history of American psychiatry.

“In the organicist tradition, the outstanding psychiatric achievement as well as the final and conclusive link in the demonstration of the etiologic role of syphilis in general paresis was Noguchi and Moore’s demonstration of the spirochete in the brains of general paretics."^[44]

Before his discovery, about 20 percent of the New York State mental hospitals were patients suffering from paresis that led to a patient’s death within five to seven years.^[44] Noguchi allowed for these patients to be diagnosed with syphilis. Noguchi proved that general paresis and tabes dorsalis are late stages of tertiary syphilis of the brain and spinal cords. Noguchi had discovered the delayed effects that could appear ten to twenty years after infection on the nervous system.^[50] In 1925, Association of American Physicians granted him its prized Kober Medal for this discovery.^[49]

When interviewed later, Noguchi said,

"All you need is enough test tubes, sufficient money, dedication, and hard work. ... and one more thing, you have got to be able to put up with endless failure."^[47]

When compared to a genius, he said, "there was no such thing as genius. There was only the willingness to work three, four, even five times harder than the next man".^[47] Dr. Noguchi's name is remembered in the binomial attached to another spirochete, Leptospira noguchii.^[5]

Noguchi was prolific in his lab results. Flexner described his work as "superhuman".^[51] His record for numbers of published papers in a single year was an unheard of nineteen submitted to journals. Noguchi published over 200 paper and gave lecture tours throughout Europe during his career.^[11]

Noguchi rarely read extensively before his experimentation. He wanted to learn through his failure.^[52] He report in a letter to his mentor,

"Theories are not to be taught by anybody outside of ourselves. We are the best teachers of the truth — I mean by this that we ought to convince ourselves chiefly by our own experiences and own experiments."^[53]

Although, he tended to draw premature conclusions. During a lecture on the transmission of syphilis to rabbits, he had been successful in only one out of thirty-six cases.^[54]

Colleagues did not understand his labeling system or lack there of for test tubes, Noguchi insisted he had it memorized.^[46] He claimed to have a "special method"^[52]

During his research on snakes, Noguchi complained about live rabbits being fed to snakes in cages and felt the practice cruel, but colleagues said he was too sensitive.^[55]

His colleagues complained about his work station covered in cigarette butts.^[56] His friend Okumura witnessed Noguchi drank and smoked a great deal, but was stunned at how Noguchi could get along without sleep.^[57]

Sometimes he was irresponsible with his specimens. Once he swallowed some solution of jaundice while pipetting a culture.^[58][59] He washed his mouth out with alcohol but he felt he might have contracted jaundice.^[59] His meticulousness made it difficult for him to accept help. He washed his own test tubes and grounded his own mixtures. He rarely slept. He once said, "I can't allow someone who doesn't know exactly what I'm doing here to interfere." This had a profound effect on his health.^[60]

Although Noguchi did not usually accept help, he met Evelyn Tilden and hired her as his secretary. In fact, she became his apprentice. Even though Tilden was a humanities major. Tilden was immensely useful for writing his research papers. Noguchi encouraged her to get an education in bacteriology. With the Rockefeller Institute's permission, she attended courses in biology and organic chemistry at Columbia University while she worked, and she made a career for herself and in 1931, received a doctoral degree, becoming professor at the North Western University.^[2]

Noguchi secretly married Mary Loretta Dardis on April 10, 1912, whom he met for a single time after he returned from Copenhagen. He did not meet her again for years, "then ran into her on the street, had a rose in his hand, held it up to her."^[61][62] Both were the same age and came from a background of poverty. Mary, nicknamed Maize, called her husband, Hidey.^[23]

The marriage was kept secret from his family, friends, and boss.^[63] Flexner opposed his marriage to an American. He thought he should marry someone of Japanese descent. Noguchi worried his marriage would put his promotion at risk because she would have to be added to his pension.^[61] Not to mention, interracial marriage was a taboo. Their marriage did become known to the public until his death.^[62] No children were born out of their marriage.^[23]

The newly married, Mr. and Ms. Noguchi, found an apartment at 381 Central Park West.^[64] He would turn his kitchen into a laboratory and put specimens in the refrigerator, have microscopes holding germ cultures on the dinner table, and test tubes kept in the oven.^[62]

Mary would read often to him at his microscope, whether it was old tales, Tolstoy, or Shakespeare.^[62][65] Mary had to endure his long absences on scientific exhibition. She would often receive daily cheap postcards occasionally with photographs tucked inside.^[62]

Noguchi would often be caught at the laboratory at night and people would ask him why he was not at home? His usual reply was, "Home? This is my home." Some people thought was escaping from his relationship but it is revealed through letters their marriage brought great satisfaction.^[66] Mary provided a refuge and inspiration.^[66]

Author Suzanne Kamata states how American women have played a large part in the success of their Japanese husbands, including Mary Dardis, but have gone unnoticed due to their nationality. Kamata argues that "one could argue that her assistance may have even helped to prolong his life" and establish her husband's legacy.^[67]

Mary saved him from financial disaster as Hideyo was notoriously bad with money.^[2] For instance, Noguchi got his salary paid in two separate checks, one to hand on to his wife and the other to keep so that he would have something to spend.^[38]

Hideyo was close friends with his neighbor, Ichiro Hori, a Japanese painter and photographer.^[61] Furthermore, Noguchi befriended Hajime Hoshi in the United States.^[18] Hoshi returned to Japan and later started a successful pharmaceutical business in Tokyo.^[18] Hoshi used his friendship with Noguchi and his reputation for his pharmaceutical company, which Hoshi offered to compensate him for. Noguchi said to give it to his family in Inawashiro.^[18]

He would write often to his mentor, Kobayashi, who granted him permission to call him "father."^[18]

His childhood mentor encouraged Noguchi to return and establish his career in Japan.^[63] In 1912, he told his family that he did not plan to return to Japan.^[68]

In a letter from his mother, Shika, who was notably illiterate, but learned to write, “Please come home soon, please come home soon, please come home soon, please come home soon.^[18]” His mother worked as a midwife, but did not have much of an income and his family was at risk of losing the family home. Noguchi began sending money every month to his family.^[69]

Shika's health declined. Noguchi sailed to visit her and accept the Imperial Prize on September 5, 1915.^[70] Noguchi was surrounded at the dock with reporters.^[70] He greeted his mentors Chiwaki and Kobayashi at the Imperial Hotel. Noguchi presented them with golden watches as gifts.^[70]

When Noguchi greeted his mother, he showed her a photograph of Mary and she approved.^[71] Noguchi spent another ten whole days with his mother, but returned to the United States, and this would be the last time he would be back in Japan.^[71] In November 1918, his mother Shika died.^[18]

In 1917, Noguchi's health had declined.^[59] Earlier Noguchi was told he had enlarged heart from his irregular intense activity after a physical examination.^[72] Mary called an ambulance since he refused to go to the hospital and was brought to Mount Sinai hospital. ^[59] He was diagnosed with typhoid fever, a severe case with perforation of his digestive tract.^[58] He claimed it was jaundice after accidentally digesting. His fever worsened and Mary and those around him thought he might die.^[19]

Hoshi financially supported him during his treatment.^[19] He made a slow recovery, Noguchi and Mary after seeing an advertisement in a newspaper took a four hour train ride to the Catskills. Both of them booked a room at the Glenbrook Hotel in the small hamlet of Shandaken, which had less than a hundred people. Noguchi felt it reminded him of his hometown in Fukushima.^[23]

Noguchi decided to purchase approximately two hectares and build a house in Shandaken, becoming one of the largest landowners in the hamlet.^[19] He bought it with the money he had leftover for his treatment.^[19] The construction was completed around June 15, 1918.^[19] Noguchi built his home alongside the Esopus river where he would fish and paint and spend most of his summers in 1918, 1922, and 1925 to 1927.^[73]

Noguchi was gifted oil paints from Ichiro Hori and he started painting in Shandaken.^[23] He had excellent success. Ichiro said, "he would be good at anything" and was not surprised at his painting ability.^[58] His paintings hang in the Hideyo Noguchi Memorial Museum.^[74]

Noguchi was an amateur photographer. It was said that there is no scientific researcher who likes photography more than Noguchi.^[75] He might have been one of the first non hand colored photographs of a Japanese person.^[75] He achieved this through using autochrome lumière. He sent this in a letter, dated August 8, 1914, to his childhood mentor, Sakae Kobayashi.^[75]

In 1911 and 1912 at the Rockefeller Institute in New York City, Noguchi was working on a syphilis skin test, which could provide an additional diagnostic procedure to complement the Wassermann test in the detection of syphilis.^[76]

Professor William Henry Welch, Board of Scientific Directors at the Rockefeller Institute for Medical Research, urged Noguchi to conduct human trials.^[76] The subjects were gathered from clinics and hospitals across New York City. In the experiment, the doctors given the tests injected an inactive product of syphilis, called luetin, under the skin on the upper arm of the patient.^[76]

Skin reactions were studied, as they varied among healthy subjects and syphilis patients, based on the disease's stage and its treatment. The lutein test gave a positive reaction almost 100 percent for congenital and late syphilis.^[77] While his diagnostic test was effective, it never had a reliable supply from the organism in pure culture form, never yielding practical results.^[49]

Of the 571 subjects, 315 had syphilis.^[78] The remaining subjects were controls; some of which were orphans between the ages of 2 and 18 years.^[78] Most were hospital patients being treated for diseases, such as malaria, leprosy, tuberculosis, and pneumonia, and the subjects did not realize they were being experimented on and could not give consent.^[78]

Critics at the time, mainly from the anti-vivisectionist movement, noted that the Rockefeller Institute violated the rights of vulnerable orphans and hospital patients. There was concern among anti-vivisectionists that the test subjects had contracted syphilis from the experiments, but were proven to be false.^[76][79]

In Dr. Noguchi's defense, Noguchi had performed tests on animals to ensure the safety of the lutein test.^[76] Rockefeller Institute business manager Jerome D. Greene wrote a letter to the Anti-Vivisection Society, which had pointed out that Noguchi had tested it on himself and his fellow researchers before administering it.^[76]

In a letter to District Attorney Charles S. Whitman, Greene said

"What public institution would not welcome a harmless and painless test which would enable it to decide in the case of every person admitted whether that person was afflicted with a venereal disease or not?"^[76]

Much of the information came from newspapers, which did not consult medical professionals.^[76] Greene mentioned the steps taken to ensure the sterility.^[76] His explanation was considered a demonstration of the care that doctors were taking in research.

In May 1912, the New York Society for the Prevention for Cruelty to Children asked the New York district attorney to press charges against Noguchi, but he declined.^[80] Although, none of subjects were infected with syphilis, the Rockefeller Institute did test on patients without consent.^[76]

Even though none of the subjects were injured in the experiment, Hideyo Noguchi had committed a wrong, it was 'a wrong without injury'.^[76]Albert Leffingwell, a physician, social reformer, and advocate for vivisectionist restrictions, said in response to Jerome D. Greene.^[76]

"If insurance could have been given that the luetin test implied no risk of any kind, might not the Rockefeller Institute have secured any number of volunteers by the offer of a gratuity of twenty or thirty dollars as a compensation for any discomfort that might be endured?"^[76]

During the period, consent in medical science was by no means customary.^[79] The United States did not develop sufficient consensus about unethical human experimentation until the late 20th century, which brought laws about involving informed consent and the rights of patients to pass.^[76]

Noguchi received incredible scrutiny. One of the newspapers described him as "the Oriental admirer of the fruits of Western civilization."^[76] He made a wrong doing with his experiments, not obtaining consent, but he might have received more criticism due to his race and the perpetuated stereotype of yellow peril.

At the same time, notable microbiologists, such as Robert Koch in 1906 to 1907 operated medical concentration camps in Africa to find a cure for sleeping sickness and blinded patients, and Louis Pasteur experimented on nine-year-old Joseph Meister without a medical license and was suspected to have lied about conducting animal trials.^[81][82] They received far less scrutiny on their legacy.

In July, 1914, Flexner made Noguchi a full member of the Institute.^[58]

His name and discoveries began to appear regularly in American newspapers.^[13] Noguchi felt compelled to make more discoveries and pressure from his boss Simon Flexner and home country to bring respect and honor to his fellow Japanese.^[83][84] He wrote in a letter,

"I am almost exhausted and I feel the weight of my situation, because every one working at this Institute is expected by the outsiders to do something. Yet, as you know, we cannot find a new thing every day!"^[85]

Noguchi began to tackle Rocky mountain spotted fever, similar to another disease Tsutsugamushi present in Japan, where deaths were common among rice planters and farmers.^[86][87] Furthermore, he began researching jaundice after two Japanese scientists announced a discovery of a spirochete appearing in the liver of a guinea pig demonstrating jaundice.^[88]

In June of 1918, Noguchi became chief investigator on a commission of the International Health Board traveled throughout Central America and South America to conduct research to develop a vaccine for yellow fever.^[89][58]

He once said, "Whether I succeed or not is another matter, but the problem is worth trying." Noguchi dabbled in researching numerous diseases at the same time. He felt one might get results.^[86]

In 1921, he was elected as a member of the American Philosophical Society.^[90] In the meantime, he was working on a revision and reprinting of Serum Diagnosis of Syphilis.^[52]

In 1923, Noguchi had attempted creating passive and active immunity for Rocky mountain spotted fever.^[52] One of his close assistants died during the research, which he mourned. He supported his assistants widow and children. ^[23] He made a breakthrough when he produced the first antiserum for the disease.^[6]

During his time in Peru and Ecuador, between 1925 to 1927, he worked on Carrions disease and verruca peruana, which was widespread in the regions, and proved the infections were due to the same species, Bartonella bacilliformis.^[50]

His assistant, Akatsu, noted Noguchi showed discontent in his career even with recent breakthroughs.^[83][91] Noguchi sometimes lost his temper and scolding his assistants, but outside of the laboratory, Noguchi was a different and more open person. He would invite him to restaurants and speak Japanese – something he never did at the Rockefeller Institute.^[64]

In a letter to Flexner, he wrote,

"Somehow I cannot manage to find enough time to sit quietly and think over things calmly and reflect upon many things and phases in life. I seem to be chasing something all the time, perhaps an acquired habit or rather the lack of poise".^[92]

Noguchi decided to focus on yellow fever, which some of his colleagues died researching because of his experience with syphilis and spirochetes.^[73][93] He thought the disease could have been a spirochete after traveling to Merida, Mexico and seeing patients demonstrate symptoms of Weil's disease, but similar to yellow fever. Noguchi identified it as Leptospira icterohemorrhagiae^[93] and mistakingly declaring it the causative agent of yellow fever.^[93] Other scientists unable to repeat his findings, it was questioned.^[93]

During his career, whether yellow fever was a virus or a bacteria was a debated topic with viruses having been discovered in 1892.^[94] Noguchi worked much of the next ten years to prove his theory that it was from spir bacteria. He even thought he developed a vaccine against it, unknowingly for Weil's disease.^[23]

Following the death of British pathologist Adrian Stokes from yellow fever in September 1927,^[95] it became increasingly evident that yellow fever was caused by a virus, not by the bacillus Leptospira icteroides, as Noguchi believed.^[23] He began preparing to travel to Accra, Gold Coast (modern-day Ghana) to study yellow fever and get closer to specimens. Noguchi believed himself immune to yellow fever because of his own vaccine.

Feeling his reputation was at stake, Noguchi hastened to Lagos to carry out additional research. However, he found the working conditions in Lagos did not suit him. At the invitation of Dr. William Alexander Young, the young director of the British Medical Research Institute, Accra, Gold Coast, he moved to Accra and made this his base in 1927.

However, Noguchi proved a very difficult guest and by May 1928 Young regretted his invitation. Noguchi was secretive, working almost entirely at night to avoid contact with fellow researchers. His erratic behavior might have been from untreated syphilis, for which he was diagnosed in 1913, which might have progressed to neurosyphilis, prone to amnesia and personality changes.^[23]

The diaries of Oskar Klotz, another researcher with the Rockefeller Foundation,^[96] describe Noguchi's temper and behavior as erratic and bordering on the paranoid. His methods became haphazard. According to Klotz, Noguchi inoculated huge numbers of monkeys with yellow fever, but failed to keep proper records.^[96] Meanwhile, his mental state deteriorated.

Despite repeated promises to Young, Noguchi failed to keep infected mosquitoes in their secure containers. In May 1928, having been unable to find evidence for his theories, Noguchi was set to return to New York after spending six months in Africa, but was taken ill in Lagos.^[23] Noguchi boarded a ship to sail home but on May 12 was put ashore at Accra and taken to a hospital. He was diagnosed with yellow fever and after some time, he died on 21 May.^[97]

During his last letters to Mary, he writes

“I spend every moment of every day waiting for a telegram from you. When I am dispirited or tired, you are the one thing that raises my spirits. I am always thinking of you. It is rare that I dream but when I do, it is always of you.” ^[98]

In a letter home, Young states, "He died suddenly noon Monday. I saw him Sunday afternoon – he smiled – and amongst other things, said, “Are you sure you are quite well?" "Quite." I said, and then he said "I don’t understand."^[99] Seven days later, despite exhaustive sterilisation of the site, Young himself died of yellow fever.^[100]

Noguchi's obituary was featured in The New York Times.^[14]

Noguchi was profoundly influential during his lifetime. Although, some of his research, including having discovered the causes of polio, rabies, trachoma, and yellow fever, were not able to be reproduced.^[101] His finding that Noguchia granulosis causes trachoma was questioned within a year of his death, and overturned shortly thereafter.^[102][103] Alongside his identification of the rabies pathogen^[104] because the medium he invented to cultivate bacteria was seriously prone to contamination.^[105]

After Noguchi's death in 1928, it would not be until the electron microscope was developed in 1931, which could identify yellow fever was a virus, even though skeptics had started to understand it was earlier.^[106]

A Rockefeller Institute researcher said that Noguchi "knew nothing about the pathology of yellow fever" and criticized him for being unwilling to issue retractions for his claims.^[107] Other critics describe it as flaws inside the system of peer review.^[108] Some of his colleagues thought Noguchi to be a brilliant scientist, who brought attention to obscure and neglected tropical diseases, such as him giving renewed attention to trachoma research, affecting a large part of developing countries in Africa.

Noguchi's most famous contribution is his identification of the causative agent of syphilis in the brain tissues of patients with partial paralysis due to meningoencephalitis.^[109] Other lasting contributions include the use of snake venom in serums, his antiserum for Rocky Mountain spotted fever, diagnostics tests, and the identification of the leishmaniasis pathogen and of Carrion's disease with Oroya fever.^[109][23]

In the 21st century, the Nobel Foundation archives were opened for public inspection and research. Noguchi was nominated several times for the Nobel Prize in Physiology or Medicine: in 1913–1915, 1920, 1921 and 1924–1927.^[12] Some of Noguchi's prize nominations and work on a pure culture of syphilis and yellow fever received scrutiny.^[110][23]

• 1904: The Action of Snake Venom Upon Cold-blooded Animals.

Washington, D.C.: Carnegie Institution. OCLC 2377892

• 1909: Snake Venoms: An Investigation of Venomous Snakes with Special Reference to the Phenomena of Their Venoms.

Washington, D.C.: Carnegie Institution. OCLC 14796920

• 1911: Serum Diagnosis of Syphilis and the Butyric Acid Test for Syphilis.

Philadelphia: J. B. Lippincott. OCLC 3201239

• 1923: Laboratory Diagnosis of Syphilis: A Manual for Students and Physicians.

New York: P. B. Hoeber. OCLC 14783533

Noguchi was honored with Japanese and foreign decorations. He received honorary degrees from a number of universities.

Noguchi was self-effacing in his public life, and he often referred to himself as "Funny Noguchi" as noted in Times Magazine. When Noguchi was awarded an honorary doctorate at Yale, William Lyon Phelps observed that the kings of Spain, Denmark and Sweden had conferred awards, but "perhaps he appreciates even more than royal honors the admiration and the gratitude of the people."^[111]

• Kyoto Imperial University, Doctor of Medicine, 1909.^[112]
• Knight of the Order of Dannebrog, 1913 (Denmark).^[113]
• Commander of the Order of Isabella the Catholic, 1913 (Spain).^[114]
• Commander of the Order of the Polar Star, 1914 (Sweden).^[115]
• Tokyo Imperial University, Doctor of Science, 1914.^[115]
• Order of the Rising Sun, Gold Rays with Rosette, 1915.^[116]
• Imperial Award, Imperial Academy (Japan), 1915.^[117]
• Central University of Ecuador, 1919, (Ecuador).^[118]
• National University of San Marcos, 1920, (Peru)
• Medicine School of Merida, "Doctor Honoris Causa en Medicina y Cirugía", 1920 (México)
• University of Guayaquil, 1919, Ecuador.^[118]
• Yale University, 1921, (United States).^[111]
• Knight of the Legion of Honour of France, 1924^[119]
• Senior fifth rank in the order of precedence, Japanese government, 1925^[119]

Noguchi's remains were returned to the United States and buried in Woodlawn Cemetery in the Bronx, New York City.^[120]

In 1928, the Japanese government awarded Noguchi the Order of the Rising Sun, Gold and Silver Star, which represents the second highest of eight classes associated with the award.^[121]

In 1979, the Noguchi Memorial Institute for Medical Research (NMIMR) was founded with funds donated by the Japanese government^[122] at the University of Ghana in Legon, a suburb north of Accra.^[123]

In 1981, the Instituto Nacional de Salud Mental (National Institute of Mental Health) "Honorio Delgado – Hideyo Noguchi" was founded with founds of the Peruvian Government and the JICA (Japan International Cooperation Agency) in Lima – Perú.^[124]

Dr. Noguchi's portrait has been printed on Japanese 1000-yen banknotes since 2004.^[125] In addition, the house near Inawashiro where he was born and brought up is preserved. It is operated as part of a museum to his life and achievements.

Noguchi's name is honored at the Centro de Investigaciones Regionales Dr. Hideyo Noguchi at the Universidad Autónoma de Yucatán.^[126]

A 2.1 km street in Guayaquil, Ecuador downtown is named after Dr. Hideyo Noguchi.

The Japanese Government established the Hideyo Noguchi Africa Prize in July 2006 as a new international medical research and services award to mark the official visit by Prime Minister Jun'ichirō Koizumi to Africa in May 2006 and the 80th anniversary of Dr. Noguchi's death.^[127] The Prize is awarded to individuals with outstanding achievements in combating various infectious diseases in Africa or in establishing innovative medical service systems.^[128] The presentation ceremony and laureate lectures coincided with the Fourth Tokyo International Conference on African Development in late April 2008.^[129] In 2009, the conference venue was moved from Tokyo to Yokohama as another way of honoring the man after whom the prize was named. In 1899, Dr. Noguchi worked at the Yokohama Port Quarantine Office as an assistant quarantine doctor.^[130]

The Prize is expected to be awarded every five years.^[131] The prize has been made possible through a combination of government funding and private donations.^[132]

• List of medicine awards
• Max Theiler – completed Noguchi's work, yellow fever vaccine (1926)
• Human experimentation in the United States
• Tōki Rakujitsu – Japanese film

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• Clark, P F (1959). "Hideyo Noguchi, 1876–1928". Bulletin of the History of Medicine. 33 (1): 1–20. ISSN 0007-5140. PMID 13629181.
• D'Amelio, Dan. Taller Than Bandai Mountain: The Story of Hideyo Noguchi. New York: Viking Press. ISBN 978-9997502384 (cloth) OCLC 440466
• Dolman, C E (1977). Hideyo Noguchi (1876–1928): his final effort. Clio medica (Amsterdam, Netherlands). Vol. 12. pp. 131–145. ISSN 0045-7183. PMID 72623.
• Flexner, James Thomas. (1996). Maverick's Progress. New York: Fordham University Press. ISBN 978-0-8232-1661-1 (cloth)
• Flexner Simon (1929). "Hideyo Noguchi: A Biographical Sketch". Science. 69 (1800): 653–660. Bibcode:1929Sci....69..653F. doi:10.1126/science.69.1800.653. PMID 17737643.
• Haniu, J (2000). "Dr. Noguchi's laboratory". Scalpel & Tongs: American Journal of Medical Philately. 44: 97. ISSN 0048-9255. PMID 11624705.
• Kita, Atsushi. (2005). Dr. Noguchi's Journey: A Life of Medical Search and Discovery (tr., Peter Durfee). Tokyo: Kodansha. ISBN 978-4-7700-2355-1 (cloth)
• Koide, S S (May 2000). "Hideyo Noguchi's last stand: the Yellow Fever Commission in Accra, Africa (1927–8)". Journal of Medical Biography. 8 (2): 97–101. doi:10.1177/096777200000800413. ISSN 0967-7720. PMID 11042776. S2CID 40772728.
• Lederer, S E (March 1985). "Hideyo Noguchi's luetin experiment and the antivivisectionists". Isis. 76 (281): 31–48. doi:10.1086/353736. ISSN 0021-1753. PMID 3888912. S2CID 27969371.
• Lederer, Susan E. Subjected to Science: Human Experimentation in America before the Second World War, Johns Hopkins University Press, 1995/1997 paperback
• Liu, Pinghui V (September 2004). "Noguchi's contributions to science". Science. 305 (5690): 1565. doi:10.1126/science.305.5690.1565a. PMID 15361606. S2CID 11983110.
• Masaki, T (1978). "[Hideyo Noguchi and oral spirochaete]". Shikai Tenbo = Dental Outlook. 51 (6): 1265. ISSN 0011-8702. PMID 394992.
• Misawa, M (1991). "[Dr. Hideyo Noguchi and Hajime Hoshi] (Jpn)". Yakushigaku Zasshi. 26 (2): 113–120. ISSN 0285-2314. PMID 11623303.
• Misawa, M (1991). "[Dr. Hideyo Noguchi and Hajime Hoshi]". Yakushigaku Zasshi. 26 (2): 113–120. ISSN 0285-2314. PMID 11623302.
• Noguerea, J J (October 2007). "Hideyo Noguchi and trachoma (Inawashiro, Japan, 1876 – Accra, Ghana, 1928)". Archivos de la Sociedad Española de Oftalmología. 82 (10): 661–662. doi:10.4321/s0365-66912007001000014. ISSN 0365-6691. PMID 17929213.
• Sri Kantha, S. "Hideyo Noguchi's research on yellow fever (1918–1928) in the pre-electron microscopic era", Kitasato Archives of Experimental Medicine, April 1989; 62(1): 1–9.
• Takazoe, Ichiro (October 2002). "[Achievement by Hideyo Noguchi]". Nippon Naika Gakkai Zasshi. 91 (10): 2887–2890. ISSN 0021-5384. PMID 12451642.
• Takeda, Yoshifumi (November 2003). "[Great Japanese bacteriologists in the Meiji, Taisho and Showa era]". Nippon Saikingaku Zasshi. 58 (4): 645–655. doi:10.3412/jsb.58.645. ISSN 0021-4930. PMID 14699855.
• "[Hideyo Noguchi – pioneer bacteriologist]". Orvosi Hetilap. 118 (4): 213–215. January 1977. ISSN 0030-6002. PMID 319394.

Wikimedia Commons has media related to Hideyo Noguchi.

• Noguchi Memorial Institute for Medical Research, University of Ghana, Legon
• Japanese Government Internet TV: streaming video, "Hideyo Noguchi Africa Prize," 2007/04/26 (5 mins.)
• Fukushima Prefecture: "The Dreamer, Hideyo Noguchi," slide show Archived 2015-08-10 at the Wayback Machine
• Cabinet Office, Government of Japan: Hideyo Noguchi Africa Prize
• Japan Society for the Promotion of Science (JSPS): Purpose and Description of the Noguchi Prize
• National Diet Library: NDL portrait
• Yomiuri Shimbun: Noguchi – slightly less than 90% name recognition amongst primary school students in Japan, 2008.