Hideyo Noguchi (1876–1928)

Hideyo Noguchi researched bacteria, including Treponema pallidum, the bacterium that causes syphilis, in Japan and the US during the early 1900s. Syphilis is a bacterial infection that spreads primarily through sexual transmission and can cause symptoms such as rashes, genital sores, and even organ damage. Noguchi recognized that Treponema pallidum causes neurosyphilis, which is when the syphilis infection spreads to the covering of the brain, the brain itself, or the spinal cord. Before Noguchi’s work, researchers knew about Treponema pallidum and the symptoms of the disease but did not know that untreated syphilis could lead to neurosyphilis. Additionally, Noguchi worked to alter and improve methods to diagnose syphilis. Noguchi’s work helped future researchers and doctors better diagnose people with syphilis and assisted them in understanding how to treat the disease’s long-term side effects.

On 9 November 1876, Noguchi was born Seisaku Noguchi to Shika Noguchi and Sayosuke Noguchi, in the town of Inawashiro, of Fukushima, Japan. At one and a half years old, he fell into a fireplace, badly injuring and burning the left side of his body. Noguchi had a disability in his left hand because of the accident. In 1883, Noguchi attended Mitsuwa Elementary School. Noguchi’s family worked as farmers but were not well off and could not afford to buy new textbooks for Noguchi. According to Yasuo Yago, the director of the Hideyo Noguchi Memorial Hall in Fukushima, Japan, despite his situation, Noguchi was a passionate, committed student and attended higher elementary school at the recommendation of his school principal, Sakae Kobayashi. Additionally, in 1892, at sixteen years old, Noguchi traveled to a town in Japan called Wakamatsu, as of 2023 referred to as the city of Aizuwakamatsu, to get surgery on his injured left hand. Kanae Wakamatsu was the surgeon who operated on Noguchi’s left hand. According to Siang Yong Tan, an emeritus professor of medicine at the University of Hawaii in Honolulu, Hawaii, and physician Jill Furubayashi, who wrote an article about Noguchi’s life, Wakamatsu inspired Noguchi to pursue a career in medicine and research.

In 1896, Noguchi moved to Tokyo, Japan, and, while working as a janitor, he studied for, took, and passed the first part of the National Medical Practitioners Qualifying Examination. Soon after, Noguchi began working at Takayama Dental School, in Tokyo. In 1897, at age twenty-one, Noguchi completed the second half of the medical practitioner exam and according to Tan and Furubayashi, he graduated with a medical degree from Tokyo Medical College in Tokyo. Immediately after graduating, he took on a lectureship and worked at Takayama Dental School, and Juntendo Hospital in Tokyo.

Also in 1898, Noguchi began working as a researcher at Kitasato Institute for Infectious Disease in Tokyo. In 1899, while working at the Institute, he met Simon Flexner, a physician and researcher who studied bacteria at the University of Pennsylvania in Philadelphia, Pennsylvania. Flexner stopped at Tokyo on his way to the Philippines. While there, Noguchi worked as Flexner’s guide and interpreter while he was in Japan. Soon after, in 1900, Noguchi left for Pennsylvania to deliver a letter to Flexner from the Kitasato Institute. While in Pennsylvania, Noguchi relied on Flexner, and Flexner helped him find living quarters and provided him with a job in his laboratory. Specifically, under Flexner, Noguchi researched the effects of snake venom on the human body, such as the destruction of red blood cells, hemorrhaging or internal bleeding, edema or swelling, and damage to the lining of blood vessels. In 1902, Noguchi continued his career by working as a pathology assistant, which is someone who conducts lab work and autopsies for researchers who investigate the causes and effects of diseases, at the University of Pennsylvania, and then in 1903, as an assistant at Carnegie Institution of Washington in Washington, D.C. In the same year, Noguchi gained a fellowship to work with Thorvald Madsen, a physician and researcher who also studied bacteria, in Copenhagen, Denmark, where he learned about serology, or the study of blood serum, which is a specific component of blood.

In 1904, Noguchi transitioned to working at the Rockefeller Institute of Medical Research, or RIMR, in New York City, New York, which, at the time, was a new research institute that Flexner was directing. There, Noguchi began studying the bacteria that cause syphilis and other diseases in more depth. Also during his time at the RIMR, in 1909, Noguchi published an extensive and detailed monograph titled Snake Venoms: An Investigation of Venomous Snakes with Special Reference to the Phenomena of Their Venoms. According to Tan and Furubayashi, that book established Noguchi’s reputation as a determined researcher at RIMR.

After 1905, Noguchi began studying syphilis and attempted to improve one of the first diagnostic tests for syphilis, a serum-based complement fixation analysis. Complement fixation analysis relies on the interaction between antigens, antibodies, and the complement system. An antigen is a foreign substance that enters the body and induces a response within the body’s immune system. An antibody is a protein that the body creates to help fight off a specific antigen, and stops antigens by binding to them. The complement system is a series of proteins in the immune system that can bind to antigen–antibody complexes to help eradicate an antigen, but cannot bind to an antigen alone. To perform a complement fixation analysis to determine whether an individual has syphilis, a scientist adds syphilis antigens and sheep red blood cells to a sample of serum from a person’s blood. If that individual has syphilis, their serum will contain syphilis antibodies, which will bind to the antigens. Then the complement system proteins will bind to the antibody–antigen complex, preventing the complement proteins from lysing the sheep red blood cells, and leaving the solution clear. However, if the patient does not have syphilis, their serum will not contain any syphilis antibodies. Thus, the added antigens will not have anything to bind to, leaving the complement proteins free to lyse the sheep red blood cells, causing the solution to turn pink. So, if a person has syphilis, the serum solution stays clear, and if a person does not have syphilis the serum solution turns pink.

In 1909, Noguchi published a paper titled “A New and Simple Method for the Serum Diagnosis of Syphilis,” that explains his modified version of an existing syphilis diagnostic test called the Wassermann test. In 1906, August Paul von Wassermann, a researcher who studied bacteria, and Albert Neisser and Carl Bruck, who both studied sexually transmitted diseases and dermatology, created what researchers typically call the Wassermann test or reaction, which involved a complement fixation analysis test using sheep red blood cells and syphilis antigens. In his 1909 paper, Noguchi explains that he found that the sheep red blood cells were unable to detect syphilis antibodies to a certain degree of accuracy in Wasserman’s test. To address that gap in accuracy, Noguchi developed a way of using human blood cells in the diagnostic test in place of sheep red blood cells, which he argues improves the accuracy, ease, and reliability of the test. In 1910, Charles F. Craig, a physician who served in the US Army Medical Corps, published an article that examined the effectiveness of Noguchi’s modifications in diagnosing those in the military. The author explains that they hope that more researchers will use the Noguchi version of the test, as they found that Noguchi’s method was slightly more accurate.

In 1911, Noguchi married Mary Dardis. According to The St. Louis Post-Dispatch Daily Magazine, Noguchi wanted to keep the marriage a secret from the Rockefeller Institute, so only close friends knew about their relationship.

In 1912, Noguchi developed another, less successful, diagnostic test for syphilis called the luetin skin test, which required physicians to inject dead syphilis cells into people’s skin. Noguchi referred to the extract of syphilis cells he created as luetin, but it was not very effective in diagnosing syphilis. Additionally, according to a piece published in 1912 in Life magazine, the luetin skin test was a large source of scandal for Noguchi as a researcher. He recruited around 400 subjects for his luetin experiment, many of whom were orphans. According to a New York Times article published in 1912, critics accused Noguchi of inducing syphilis in many of his child subjects and taking advantage of their social situation to use them as test subjects. Many critics, such as the anti-vivisectionists, a group dedicated to preventing animal cruelty and promoting ethical research, criticized Noguchi even though he denied their claims. According to Susan Lederer, who studies the history of medicine, Noguchi’s colleagues attempted to defend him by explaining that he tested luetin on animals, and then on himself, prior to injecting it into his test subjects, but that did little to calm the public. As of 2023, governmental institutions such as the Office for Human Research Protections protect against and prohibit research on vulnerable populations such as children, but at the time of Noguchi’s experiments, those laws were not in place. According to Lederer, in 1912, the New York Society of the Prevention for Cruelty of Children asked the District Attorney of New York to press charges against Noguchi, but the District Attorney declined.

In 1913, Noguchi published an article that described how he found the bacterium Treponema pallidum in patients suffering from paresis, or dementia. At the time, the term paresis was often associated with neurosyphilis, or syphilis infection of the central nervous system, that results from untreated syphilis. Noguchi found Treponema pallidum in the brains of his patients with paresis. Flexner assisted in confirming the identity of the bacteria in the samples to ensure that Noguchi’s results were indeed accurate. Before Noguchi’s work, researchers knew the immediate symptoms of syphilis but did not know about the long-term effects of syphilis infection, especially on the brain and spinal cord. They also knew about paresis and its symptoms, but Noguchi connected the two diseases and made it clear that a syphilis infection is one of the causes of paresis.

While researchers in the twentieth and twenty-first centuries praise Noguchi and his successes in syphilis research, researchers also criticize him for his inaccurate and frantic research practices. According to Tan and Furubayashi, Noguchi contracted syphilis himself, and some believe that Noguchi’s syphilis may have progressed to neurosyphilis, causing his erratic, paranoid behavior, and inaccurate research. In addition to earlier controversy surrounding the luetin test, in 1918, Noguchi took a trip to Ecuador, where he became interested in yellow fever and again embroiled in controversy. Yellow fever is a viral illness often seen in tropical regions such as South America and Africa. Mosquitos spread the disease to people. Yellow fever causes fever, muscle aches, and even organ failure. Noguchi found small amounts of the bacteria Leptospira iceteroids in a few of the yellow fever patients he studied and inaccurately concluded that the bacterium caused yellow fever. In the 1920s, scientists established that yellow fever was a viral illness and, according to Tan and colleagues, many researchers criticized Noguchi for his inadequate record keeping and bad research methods.

In 1927, Noguchi left for Africa in an attempt to confirm his findings regarding the cause of yellow fever. Noguchi conducted research and extended his initial stay from three months to six months but ended up falling ill with yellow fever.

Despite his difficulties later in life, Noguchi broadened researchers’ and patients’ knowledge of syphilis by modifying diagnostic tests for it, which physicians and scientists improved upon in the decades after its development. For example, in 1954, scientists developed a complement fixation analysis test that used three types of antigens and, thus, could simultaneously detect whether someone had syphilis, tuberculosis, or Chagas Disease. Tuberculosis is a highly contagious bacterial infection that mainly targets the lungs, and Chagas Disease is spread through a parasite that can cause serious heart damage. That test allowed physicians to screen for all three diseases at once in areas where they were all prevalent. 

Additionally, as of 2023, because of Noguchi’s work, physicians and scientists know about the long-term neurological complications of syphilis, and they have conducted further research to improve treatments for neurosyphilis. In 1928, Alexander Fleming discovered the antibiotic penicillin, and published his work on it in 1929. In the 1940s, physicians found that after the use of penicillin, the cases of neurosyphilis decreased. In the late 1920s, researchers noted that 9.5 percent of individuals developed neurosyphilis, but in 2021, researchers found that 1.7 to 1.8 percent of syphilis patients developed neurosyphilis.

During his lifetime, researchers nominated Noguchi many times for a Nobel Prize, but he never won. However, he won other honors during his lifetime. In 1928, the Japanese government posthumously awarded Noguchi the Order of the Rising Sun, Gold and Silver Star, the second highest award that the government typically gives individuals who contribute heavily to fields of study outside the military. In 1979, the Japanese government also established the Noguchi Memorial Institute for Medical Research, a biomedical research institute in Accra, Ghana. In 2006, the Japanese government created the Hideyo Noguchi Africa Prize to honor and fund scientists who contributed to infectious disease research in Africa. As of 2023, Noguchi’s image is printed on 1000-yen notes, which is lowest cost banknote in Japan’s currency.

Noguchi died on 21 May 1928 of yellow fever in Accra, Ghana.