Even though researchers had shown in 1943 that penicillin was effective against syphilis and gonorrhea, there remained doubts about how the disease could be prevented and treated. Sexually transmitted diseases were recognized to be a first-order threat to the health of servicemen during World War II. Postcoital urethral lavage with a silver solution to prevent gonorrhea and genital application of a cream to prevent syphilis were methods that had been in use for decades, but they were troublesome, painful, and of slight effect.3

In the United States, doctors under the direction of John C. Cutler had begun experimenting on US prisoners,4 and after some preliminary studies they developed a more ambitious plan to expose healthy subjects to infection by prostitutes. This would be a study they knew could not be done in the United States, however, as public opinion would not have tolerated it if it came to light. In 1945, Juan Funes, a Guatemalan military doctor who had worked at the Venereal Disease Research Laboratory (VDRL) at an American prison for a year, offered to help them carry out the studies in Guatemala.5

The US officials involved in designing and carrying out the study were affiliated with the VDRL, which operated under the US Public Health Service (USPHS), an entity that later became the Center for Disease Control and Prevention (known as the CDC). They worked in collaboration with Guatemalan researchers6 and the Pan-American Sanitary Bureau (PASB), the predecessor of the Pan American Health Organization. Cutler was in charge. Under him were 2 other doctors: Robert C. Arnold and John F. Mahoney, who were also affiliated with the VDRL and the USPHS. In Guatemala they had the help of Juan Funes, chief of the Division for Control of Venereal Diseases, which operated under the Guatemalan public health office. Staff at the Ministry of Health and other government departments were also involved, along with military personnel.

Why was Guatemala chosen? One factor influencing the decision was that prostitution was legal in the country and its prisons. Everything related to prostitution, contagion, and the treatment of infected patients was the responsibility of the Division for Control of Venereal Diseases, headed by Funes, who was among the investigators. An agreement was drawn up stating that once the PASB's interest in the project ended, the equipment and laboratories set up in Guatemala would be transferred to the government, becoming public facilities operated by local staff.

Experimentation began in the Guatemalan prisons. Contact with infected prostitutes proved to be an unreliable means of inoculation, however. Furthermore, follow-up serology data were incomplete because the prisoners objected to periodic extractions.

The study design was therefore revised so that experiments could target a different population: patients residing at a public mental health facility (Hospital Nacional de Salud Mental). The mental condition of these patients meant that they offered no resistance,7 and since the government facility had evident deficits, the US researchers were able to obtain institutional cooperation by promising needed material and offering patients cigarettes as compensation for their cooperation.8,9

Cutler arrived in Guatemala in 1946 to begin experiments that included serology and tests to confirm the true efficacy of penicillin in clinical use and evaluate the various preventive strategies10–12 (Fig. 1).

Figure 1.

Records for a prisoner in Guatemala, from the John C. Cutler archive. Source: National Archives and Records Administration, United States.

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The USPHS was interested in studying so-called normal exposure. Their initial attempt at using infected prostitutes to spread gonorrhea among the soldiers and prisoners required them to first inoculate the prostitutes with germs cultured in rabbits. Statistics at the time assumed that a single prostitute could have sex with 8soldiers in 71minutes, so the potential for contagion was, in theory, enormous.13

Cutler found it was difficult to introduce infection by these naturalistic methods, however, so it was decided to resort to direct inoculation. The site of this attempt would be the Guatemalan government's mental health facility, where patients would be acquiescent. The researchers abraded the subject's penis to increase the likelihood of infection, and they injected syphilis into the spinal fluid of some.13 The bacteria they used came from other patients who were already infected or from “street strains.”14 The consent of patients or their families was, of course, never obtained. Permission was only asked of the military officers in command or administrators and doctors at the facility.15 Deaths occurred during the experiments on the psychiatric patients, but were attributed to the high rate of underlying disease.

The study ended in 1948, although some follow-up laboratory testing and other procedures, such as tissue sampling and autopsies, went on for years. Autopsies of patients on whom the experiments had been done were being practiced even as late as 1958. The study was never covered up: results were presented at the the Second Central American Venereology Conference in Guatemala City in April 1948, for example, and some were published in the journal Salubridad y Asistencia an organ of the Ministry of Public Health and Social Services (see volume II, the issue for April 4–7, 1949).9,13

Performing serologies was one of the hurdles the experimenters faced. Techniques that had been recently described were available, and studies were done in a broad spectrum of the Guatemalan population, in orphanages, and in leprosy hospitals.16 A training course given by the US scientists for their Central American colleagues was attended by participants from Guatemala, El Salvador, Costa Rica, and Panama. In the summer of 1949, all the course participants were asked to provide the trainers with blood samples from patients, and the response was very positive: 1073 were sent from Guatemala, 1007 from El Salvador, 1295 from Costa Rica, and 1899 from Panama.13

The material documenting the Guatemalan experiments, which are part of the John C. Cutler papers deposited at the University of Pittsburgh, were recently released for examination. The papers include extensive summaries describing the syphilis experiments and briefer notes about gonorrhea and chancroid studies, as well as correspondence, records, and the patients’ clinical data.17

The work in Guatemala was halted in 1948 for reasons left unclear, and it was not brought to light until Reverby's chance discovery in 2010. Once the documents were made public, they were analyzed by various investigative commissions and a fairly credible account could be reconstructed to clarify what happened and when. The physicians had taken advantage of their position to experiment with vulnerable members of society, who in this case were the mentally ill, members of indigenous groups, men who had enlisted in the military, and prostitutes.18

In the first third of the 20th century the medical literature often contained the claim that syphilis tended to have greater impact on the nervous system in Caucasian populations, whereas the cardiovascular system was more vulnerable in persons of black African descent. However in a study of hundreds of untreated cases in white men in Oslo, published by E. Bruusgard in 1928, the authors found the rate of cardiovascular involvement to be higher and they uncovered very few cases of neurosyphilis.28,29 A similar prospective study was then planned in the United States. It was to be carried out in an area of Alabama with a high prevalence of syphilis, where 35% to 40% of the population was seropositive. Taliaferro Clark seems to have proposed the idea of observing untreated syphilis for 6 to 8 months, after which the patients would be treated with the standard resources of the day, including Salvarsan30 and bismuth.31 This once common regimen was effective, although it was also fairly toxic.

The researchers enrolled 600 African American men in Macon County, Alabama (Fig. 2); 399 of them had previously contracted syphilis and 201 were healthy controls. The participants were largely illiterate and they were offered free medical care, a meal every day, and a $50 burial policy for funeral expenses. The men were not told they had syphilis, nor were they treated. The cost of their health care was covered by the Julius Rosenwald Fund32 until events related to the crash of 1929 forced the fund to withdraw support.

Figure 2.

Conducting a physical examination during the Tuskegee study. Source: National Archives and Records Administration, United States.

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The Tuskegee study kept going, however; it seems that some researchers wished to have a longer period of observation. Dr. Clark disagreed with the change of plan and withdrew the same year his study had commenced.

The subjects were never properly informed, but the researchers also resorted to deception to win cooperation. To ensure the men would come for spinal taps, one of the supervisors, Raymond A. Vonderlehr, sent each man an untruthful letter with the phrase “Remember This Is Your Last Chance For Special Free Treatment.” Furthermore, permission for autopy was obtained by making the burial policy contingent upon agreeing to it. The researchers were obsessed with obtaining data for science above any ethical considerations.33 The study was never kept secret: a great deal of information and many articles were published while it was under way.33–37

The greatest contribution connected with Tuskegee was the development and standardization of diagnostic serum tests for syphilis. Publications began to appear in 193438 and 1935.39 When the first study comparing treated and untreated men with syphilis was published a year later, nontreponemal diagnostic tests were already in use.40 The 1936 paper specifically emphasized the incidence of cardiovascular involvement in the Tuskegee population. Starting in 1942, the USPHS used sera from Tuskegee to develop the VDRL test.41

The Tuskegee techniques were instrumental in establishing the USPHS's position in international health organizations. Research on serologic techniques and the lucrative commercialization of diagnostic tests allowed the service to occupy a place beside German research programs, which had pioneered this field, and to occupy a respected position in the World Health Organization.

Fleming's initial discovery of penicillin had been made in 1928, and American military doctors were already using it to treat servicemen for syphilis in the Pacific in 1943.42 Penicillin was evidently effective, and by 1947 it had become the gold standard treatment for the disease. This new drug was so successful that by the mid-1950s the incidence of syphilis had plummeted and many believed it might be eradicated entirely.43 The Tuskegee experiment nonetheless pushed on. The subjects enrolled were neither given penicillin nor told of this treatment so that the researchers could continue to watch how the disease progressed and killed. Treatment was deliberately denied to many and they were also specifically warned to avoid taking penicillin.

Even as the US government sponsored public health campaigns that aimed at eradicating syphilis, the Tuskegee men were carefully shielded from information. During World War II, 250 men drafted into the armed forces were diagnosed. Their military doctors recommended treatment, but by order of the USPHS, the recommendations never reached the men. In 1951, public health authorities still insisted that the Tuskegee experiment constituted a “unique opportunity”29 (p. 179).

The Nuremberg Code of 1947, the Catholic Church's position expressed by Pope Pius XII in 1952, and the Declaration of Helsinki of 1964 all insisted that researchers must hold the well-being of the individual before any interests of medical experimentation, that participation in research must be voluntary, and that subjects must be fully informed before consent can be given.44 None of these voices deterred the Tuskegee researchers, who pushed on relentlessly, unaffected by all ethical decrees and the maturing conscience of both science and society with respect to moral issues.

When the lay press focused attention on Tuskegee in 1972, the authorities were finally moved to close down the Tuskegee experiment. Voices had begun to warn of unethical practices in the study, which was now in its final phase. The CDC reiterated its position that work should continue until all the patients had passed on so that autopsies could be performed.

It was Peter Buxtun (sometimes Buxton) who first approached the press with concerns about Tuskegee in the early 1970s; the story was published in The Washington Star on July 25, 1972, and a day later it made the front page of The New York Times. The scandal moved Senator Edward Kennedy to organize Congressional hearings. Strong public protest followed and an advisory group determined that the study was medically unjustified and ordered it shut down. The Tuskegee experiment had lasted 40 years and only 74 men were still alive. Twenty-eight of the 399 subjects had already died of syphilis and 100 had died of complications. Forty women, partners of men in the study, had been infected and 19 children had been born with congenital syphilis.

The authors state that no experiments were performed on humans or animals for this investigation.

The authors declare that they have followed the protocols of their hospitals concerning the publication of patient data and that all the patients included in this study were appropriately informed and gave their written informed consent.

The authors declare that no patient data appear in this article.