us guatemala std experiments

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• Introduction

Basis for the experiments

Study design.

• Study flaws and ethical considerations

Guatemala syphilis experiment

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• U.S. Department of Health & Human Services - act Sheet on the 1946-1948 U.S. Public Health Service Sexually Transmitted Diseases (STD) Inoculation Study
• Nature.com - Human Experiments - In the 1940s, US doctors deliberately infected [...]
• National Public Radio - U.S. Apologizes For Syphilis Experiments In Guatemala
• The National Security Archive, Unedited and Uncensored - Decades Later, NARA Posts Documents on Guatemalan Syphilis Experiments
• Table Of Contents

Guatemala syphilis experiment , American medical research project that lasted from 1946 to 1948 and is known for its unethical experimentation on vulnerable human populations in Guatemala . The intent of the study was to test the value of different medications, including the antibiotic penicillin and the arsenical agent orvus-mapharsen, in the prevention of symptom emergence following infection with certain sexually transmitted diseases (STDs). A diagnostic testing arm of the study investigated methods to refine STD screening techniques. The total study population included more than 5,500 Guatemalan prisoners, sex workers, soldiers, children, and psychiatric patients, about one-quarter of whom were deliberately infected with syphilis , gonorrhea , or chancroid and all of whom were enrolled in the experiments without their consent.

At the start of World War II , U.S. medical researchers were tasked with finding an effective strategy for preventing the contraction of STDs among soldiers who consorted with prostitutes. The first such strategy emerged in the early 1940s, when government scientists discovered that penicillin could eliminate symptoms of syphilis within days of infection. The U.S. military subsequently began using penicillin as a means of post-STD-exposure treatment. However, it was unclear whether penicillin provided long-term prophylactic protection and whether it could be used in a similar manner for other STDs. In addition, its supplies were limited, and scientists were interested in testing the prophylactic ability of other agents, including orvus-mapharsen, which could be applied as a foaming wash following exposure. Hence, the Guatemala study was proposed.

The Guatemala experiments were designed based on the Terre Haute prison experiments of 1943–44, which were carried out in consenting prisoners at a penitentiary in Terre Haute , Indiana. Intended to test preventative strategies for gonorrhea, the Terre Haute study ultimately failed to meet its goals because of difficulties with establishing the infection in subjects. As a result, testing different inoculation methods for gonorrhea, syphilis, and chancroid formed a major part of the Guatemala experiments. Among the most controversial methods used was “normal exposure,” in which sex workers infected with syphilis were used to transmit the disease to unsuspecting prisoners.

Much of the diagnostic and laboratory work was carried out at a 300-bed hospital in Guatemala City that had been built specifically for the study. The city was chosen as the study site in part because it housed a relatively large population of prisoners and other potential test subjects. Directing the research was United States Public Health Service (USPHS) scientist John C. Cutler, who had been involved in the Terre Haute study and who later was one of the leaders of the Tuskegee syphilis study . Cutler and USPHS colleagues collaborated with local Guatemalan physicians and were granted access to public health centres, government hospitals, mental institutions, and orphanages as a result of negotiations between the Pan American Sanitary Bureau (PASB; now Pan American Health Organization) and the Guatemalan government.

Approximately 1,308 soldiers, prisoners, sex workers, and psychiatric patients, ranging from age 10 to 72, were intentionally exposed to STDs during the study. Syphilis exposure occurred through inoculation of the cervix in sex workers; through injection or direct sexual contact with infected sex workers in prisoners; and through injection, inoculation (via abrasion) of the penis , cisternal puncture (the insertion of a needle below the occipital bone at the back of the skull to access cerebrospinal fluid ), or oral ingestion in psychiatric patients. Exposure to gonorrhea was carried out in sex workers through cervical inoculation and in Guatemalan soldiers through sexual contact with the sex workers and sometimes through urethral inoculation; psychiatric patients were infected through inoculation of the urethra , rectum , or eyes . Chancroid was transmitted to Guatemalan soldiers and psychiatric patients through abrasion and rubbing of inoculum into the skin on the arms or back.

Serology testing, in which blood and spinal fluid samples were collected for the detection of antibodies and microorganisms indicative of infection, was performed in 5,128 subjects (some of whom were involved in the intentional infection arm of the study). Subjects included children as young as one year, persons with leprosy , psychiatric patients, and personnel stationed at the U.S. Air Force base in Guatemala. This phase of the research, intended to refine diagnostic techniques for STDs, lasted until 1953.

As a measure of “goodwill” toward the Guatemalan government but also to promote the prophylaxis study, Cutler initiated an STD treatment program. About 820 subjects received some form of treatment for their infections; more than 650 of these individuals were in the deliberate exposure group.

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• v.96(2); 2018 Jun

From in vivo to in vitro : How the Guatemala STD Experiments Transformed Bodies Into Biospecimens

Kayte spector‐bagdady.

1 Center for Bioethics and Social Sciences in Medicine, University of Michigan Medical School

PAUL A. LOMBARDO

2 Center for Law, Health and Society, Georgia State University College of Law

Policy Points:

• While most scholarship regarding the US Public Health Service's STD experiments in Guatemala during the 1940s has focused on the intentional exposure experiments, secondary research was also conducted on biospecimens collected from these subjects.
• These biospecimen experiments continued after the Guatemala grant ended, and the specimens were used in conjunction with those from the Tuskegee syphilis experiments for ongoing research.
• We argue there should be a public accounting of whether there are still biospecimens from the Guatemala and Tuskegee experiments held in US government biorepositories today. If such specimens exist, they should be retired from US government research archives because they were collected unethically as understood at the time.

The US Public Health Service's Guatemala STD experiments (1946‐1948) included intentional exposure to pathogens and testing of postexposure prophylaxis methods for syphilis, gonorrhea, and chancroid in over 1,300 soldiers, commercial sex workers, prison inmates, and psychiatric patients. Though the experiments had officially ended, the biospecimens collected from these subjects continued to be used for research at least into the 1950s.

We analyzed historical documents—including clinical and laboratory records, correspondence, final reports, and medical records—for information relevant to these biospecimen experiments from the US National Archives. In addition, we researched material from past governmental investigations into the Guatemala STD experiments, including those of the US Presidential Commission for the Study of Bioethical Issues and the Guatemalan Comisión Presidencial para el Esclarecimiento de los Experimentos Practicados con Humanos en Guatemala.

Identified spinal fluid, blood specimens, and tissue collected during the Guatemala diagnostic methodology and intentional exposure experiments were subsequently distributed to laboratories throughout the United States for use in ongoing research until at least 1957. Five psychiatric patient subjects involved in these biospecimen experiments died soon after experimental exposure to STDs. The same US government researchers working with the Guatemala biospecimens after the exposure experiments ended were also working with specimens taken from the Tuskegee syphilis study.

Conclusions

There should be a complete public accounting of whether biospecimens from the Guatemala and Tuskegee experiments are held in US government biorepositories today. If they still exist, these specimens should be retired from such biorepositories and their future disposition determined by stakeholders, including representatives from the communities from which they were derived.

O n january 7, 1957, dr. john c. cutler, then a senior surgeon in the United States Public Health Service's (PHS) Venereal Disease Division, requested 9 tissue samples from his colleague Dr. Llewellyn Lee Ashburn, chief of the section on pathology and anatomy at the National Institutes of Health (NIH). Cutler described the material as “autopsy and biopsy material” connected to his “former research project.” 1 Cutler listed all of the donors by full name and subject number and identified whether the sample was from the subject's urethra, skin, or cervix. He asked that the biospecimens be sent to Dr. James D. Thayer at the University of North Carolina, Chapel Hill's (UNC) Venereal Disease Experimental Laboratory (VDEL) for use in his gonorrhea research. 1 (See Table 1 for a list of the key players and their affiliations.)

Key Players in the Biospecimen Experiments a

Cutler would later become notorious for his involvement in the PHS STD experiments conducted in Guatemala from 1946 to 1948, which drew media attention and public ire in 2010 when the records were disclosed. 2 Ashburn would have been familiar with this research, as he was in Guatemala conducting his own research on river blindness at the same time as Cutler. 3 The intentional exposure experiments were initially designed to test postexposure prophylaxis for syphilis, gonorrhea, and chancroid. These experiments ultimately involved exposing more than 1,300 soldiers, commercial sex workers, prison inmates, and psychiatric patients to STDs without their consent or sometimes even knowledge. PHS and Guatemalan researchers used injections and other invasive interventions to intentionally expose these subjects to infectious disease; only half of the subjects received any subsequent treatment for potential infection. 4

Thayer, the recipient of the biospecimans in 1957, had previously worked at the Venereal Disease Research Laboratory (VDRL) in Staten Island with Cutler and his supervisors. 5 The samples Thayer requested were collected during the Guatemala STD experiments from 4 men and 4 women—all patients from the Asilo de Alienados, a psychiatric hospital in Guatemala City. 6 Cutler sent these tissue samples from Guatemala to the NIH. He noted in 1956 that they had been “up to eight years in formaldehyde,” indicating they were collected before he left Guatemala in 1948. 7

The Guatemala intentional exposure experiments have already been scrutinized in several publications. Analysis of those experiments by historian Susan Reverby resulted in government‐led investigations by the US Centers for Disease Control and Prevention (CDC), 8 President Obama's Presidential Commission for the Study of Bioethical Issues (Bioethics Commission), 4 and the government of Guatemala. 9 , 10 , 11 Other related scholarship has explored how the intentional exposure experiments were approved, 12 critiqued the Bioethics Commission's report, 13 reviewed the history of the NIH's regulatory structure, 14 called for compensation for victims, 15 and evaluated the legacy of associated physicians. 16 But there were actually 3 types of experiments being conducted by US government officials and their Guatemalan counterparts during this time period:

• Diagnostic methodology experiments : Taking blood and spinal fluid to test the sensitivity and specificity of syphilis diagnostic methodologies.
• Intentional exposure experiments : Intentionally exposing subjects to syphilis, gonorrhea, and/or chancroid as part of a larger protocol which included testing the effectiveness of prophylaxis and treatment methods.
• Biospecimen experiments : Collecting and experimenting with identified spinal fluid, blood, and tissue specimens from research subjects in the diagnostic methodology and intentional exposure experiments, even after the Guatemala STD experiment grant funding ended.

The Bioethics Commission discussed the diagnostic methodology and intentional exposure experiments in its 2011 report but only briefly acknowledged the biospecimen experiments. 4 (p83) This article is therefore the first to explore how the subjects from the diagnostic methodology and intentional exposure experiments played one last role in the Guatemala STD experiments: as unknowing secondary research subjects for blood, tissue, and/or spinal fluid experiments. The biospecimens collected from the Guatemalan subjects were subsequently distributed to laboratories throughout the United States for use in this ongoing research. 7 , 17

The current disposition of the Guatemala biospecimens is particularly significant as in July 2018, major revisions to the current US human subjects protection research regulations became effective. 18 This was the first major revision of regulations initially conceived in the 1970s as a response to federally funded research scandals, most notably the Tuskegee syphilis experiments (in which PHS researchers observed poor black sharecroppers with syphilis in Macon County, Alabama, for decades and prevented them from receiving treatment). 19 The most significant controversy surrounding the revisions to these research regulations involved informed consent to research with human specimens. 20

Here we first review the relevance of the Guatemala intentional exposure and diagnostic methodology experiments to the subjects who later became part of the biospecimen experiments. The US government researchers who conducted those experiments in Guatemala were the leaders of the venereal disease research movement for the first two‐thirds of the 20th century; many of the same men who approved the intentional exposure experiments as members of the NIH Syphilis Study Section later benefited from that approval by engaging in the biospecimen experiments, 12 and some of those scientists were also simultaneously working with samples taken from the Tuskegee syphilis study.

While the Guatemala biospecimen experiments are historically important in their own right, we believe they can also inform current policy discussions concerning research involving biospecimens. Our ethical and regulatory entities still struggle with the appropriate normative framework with which to approach the research use of such specimens—particularly those that have been obtained through improper means. Here we argue that there should be a complete public accounting of whether biospecimens from the Guatemala and Tuskegee experiments are held in US government biorepositories today. If they still exist, these specimens should be retired from such biorepositories and their future disposition determined by stakeholders, including representatives from the communities from which they were derived.

The Guatemala STD Experiments

Intentional exposure experiments.

The original research grant for the “Guatemala study dealing with the experimental transmission of syphilis to human volunteers and improved methods of prophylaxis” 21 supported intentional exposure experiments that ran from February 1947 through October 1948. 4 (p127) During this time period, Cutler collected from psychiatric patients the biospecimens that Thayer would later request. It is possible to review the de‐identified research records of these subjects via the Bioethics Commission's Guatemala Subject Data Spreadsheet , 6 as well as from material published by the Guatemalan government's Comisión Presidencial para el Esclarecimiento de los Experimentos Practicados con Humanos en Guatemala. 9 , 10 , 11 Through these records we know that these subjects endured some of the most severe experimental exposure interventions documented.

Subjects who later were involved in the Guatemala biospecimen experiments were exposed to syphilis, gonorrhea, or chancroid during the intentional exposure experiments; 2 of the subjects were exposed to more than one STD (Table 2 ). Methods of exposure included inserting a toothpick coated in gonorrheal pus (taken from another patient) deep into the urethra or into the eyes. Syphilitic emulsion was injected into subjects’ arms (Figures ​ (Figures1 1 and ​ and2) 2 ) or rubbed into their intentionally abraded genitals. Only 2 of the 8 subjects have any record of being treated for these exposures. Five of the subjects died during the intentional exposure experiments and were given autopsies by staff at the psychiatric hospital. No information regarding death or autopsy results is available for 2 patients. One patient was discharged from the institution, with the record indicating that she had been “freed” (see Table 2 ).

Photo of Syphilitic Chancre on Arm of Female Psychiatric Patient and Subject of the Biospecimen Experiments 

Photo of syphilitic chancre (dated 12/30/1947) on right arm of female psychiatric patient 0341 after exposure to syphilis via injection during the intentional exposure experiments (public domain); 22 related clinical notes state she was “freed” in December of 1949; a sample of her skin was later requested for the biospecimen experiments (Table 2 ). [Color figure can be viewed at http://wileyonlinelibrary.com ]

Portrait of Male Psychiatric Patient and Subject of the Biospecimen Experiments 

Portrait of male psychiatric patient 0432 11(p228) (public domain); he was exposed to syphilis 8 times via the contact method and injection over the period of a year during the intentional exposure experiments; a sample of his skin was later requested for the biospecimen experiments (Table 2 ).

Biospecimans From the Intentional Exposure Experiments Involved in the Biospeciman Experiments a

Of the 5 patients whose deaths were recorded, all died proximate to the time in which they were involved in the intentional exposure experiments (see Table 2 ). The Bioethics Commission reported 83 deaths of subjects during the Guatemala STD experiments but found that “the exact relationship between the experimental procedures and the subject deaths is unclear.” 4 (p42) Cutler claimed in his later report that this “steady loss of patients by death” was primarily due to high rates of tuberculosis and the fact that “acute and chronically ill patients were used.” 4 (p42)

Diagnostic Methodology Experiments

In addition to the biospecimens that Cutler collected himself during the intentional exposure experiments, specimens were also mailed to the United States by additional PHS and Guatemalan researchers. 4 (p83) For example, Genevieve Stout, a PHS microbiologist and serologist who worked for VDRL director John F. Mahoney, moved from the VDRL to act as the director of the Guatemala City laboratory, where she conducted diagnostic methodology experiments of her own. 4 (p82), 23 , 24 , 25 , 26 , 27 The VDRL in Chamblee, Georgia, cosponsored this research and served as a control laboratory for some of the work. 28

In addition to Stout, the PHS continued to support several local Guatemalan staff after the Guatemala STD grant ended. Cutler wrote that he and Dr. Sacha Levitan (also a PHS senior surgeon and the “assistant director” of the intentional exposure experiments) felt that continued observation of the Guatemala intentional exposure subjects was critical. 29 Cutler recommended Dr. Juan M. Funes (his former PHS fellow in the United States and chief of the VD Section of the Guatemalan Ministry of Public Health) and Dr. Carlos Salvado (the director of the Guatemalan psychiatric hospital) to supervise the ongoing research. 29 These doctors and several staff were offered part‐time salaries from the PHS Venereal Disease Division for “post‐treatment” observation of the subjects, and additional funds were set aside to pay for cigarettes to reward subjects and to support autopsies. 29 , 30 Medical records were also updated and provided to Cutler, who kept them in a personal record collection. 31 Funding was specifically allocated for preparation and shipment of biospecimens to the Staten Island VDRL. 30 Payments from the Venereal Disease Division to the Guatemalan physicians ended in May/June 1950, 32 although they shipped biospecimens to the United States until at least 1953. 17

While the PHS employment contract for Funes indicated that the ongoing research would be with patients—including orphans, schoolchildren, prisoners, and indigenous communities—and those released from the psychiatric institution, 30 the single available contemporaneous report is actually a record of diagnostic methodology experiments involving 243 blood draws and 170 lumbar punctures collected exclusively from 248 institutionalized psychiatric patients. 4 (p83,n628) While all of these subjects were described as “post‐treatment,” the diagnostic records provided with the samples demonstrate that 30 patients still tested positive for syphilis by at least one diagnostic metric (Online Appendix). 17 We found no record that these patients received any additional treatment.

Biospecimen Experiments

Biospecimens from people with STDs, such as the ones sent from Guatemala, were a highly valued commodity during Cutler's time in Guatemala and the decade thereafter. Serologic testing of blood was the backbone of syphilis diagnosis and control, but—as in Guatemala—researchers were still studying appropriate diagnostic methodologies into the 1950s and beyond.

In a 1995 article, Benjamin Roy argued that the primary goal of the Tuskegee syphilis experiments had not been, in fact, to observe the natural progression of syphilis, as the clinical publications claimed—but rather to develop serological testing for the US commercial market. 33 As a result of significant increases in federal funding for syphilis eradication from the 1930s through the 1950s, the market for STD testing grew into a lucrative business during the years that encompassed the Tuskegee and Guatemala experiments, as the number of people being tested rose rapidly. 33 Laws requiring syphilis testing for “marriage certificates, newborns, military recruits, industrial physical examinations, and admissions to hospitals” ensured steady work for laboratories. 33 (p64) To support the diagnostic research necessary to do this kind of testing, Tuskegee syphilis experiment researchers sent biopsy material, medical records, X‐rays, and autopsy spinal/brain samples to researchers at the NIH and universities like Johns Hopkins and UNC–Chapel Hill (where Thayer worked using PHS funds). 7 , 19 (pp148‐149), 34 In 1970, James Lucas, assistant chief of the venereal disease branch of PHS, claimed that the only scientific benefit of the Tuskegee syphilis experiments was the development of STD diagnostic methodologies. 19 (p202)

Stout, Funes, and Cutler also sent several different kinds of biospecimens from the Guatemala experiments to the same biorepositories that housed the Tuskegee materials. But, unlike the Tuskegee syphilis experiments which resulted in many publications (one of which included Cutler as a coauthor 35 ), data from the Guatemala intentional exposure experiments were never published. 4 (p86) We also found no evidence that work from the biospecimen experiments was described in peer‐reviewed publications.

One of the few extant records confirms that Funes, the Guatemalan physician paid by the US government to conduct diagnostic methodology experiments, mailed blood and spinal fluid specimens to the Chamblee, Georgia, VDRL in 1953. There, the biospecimens were received by VDRL associate director Dr. W.F. Edmundson, assistant director Ad Harris, and Cutler. 17 VDRL director Dr. Sidney Olansky—who at the time was the director of the Tuskegee syphilis experiments 19 —was also listed on the Guatemala biospecimen manifest. 17 Edmundson was also simultaneously working on “serologic reactions in untreated syphilitic male Negroes” to determine “specific morbidity and mortality of latent syphilis in a group of untreated male Negroes” in Macon County, Alabama (ie, the Tuskegee experiments). 36 In another study, Edmundson, Olansky, Harris, Cutler, and Dr. Harold J. Magnuson (the director of the UNC VDEL who recruited Thayer) coauthored a paper on a protocol of US prisoners who were experimentally exposed to syphilis—evidence of the close working relationship of these researchers and overlapping use of STD specimen collections. 37

In October 1956, 3 years after the biospecimens were sent from Guatemala, Thayer met with his former VDRL colleague Cutler at a scientific conference in Washington, DC. 38 , 39 At that meeting, Cutler informed Thayer that biospecimens obtained from 9 subjects in Guatemala and brought back to the United States were available for research. 7 Upon return to the UNC VDEL in 1957, Thayer requested access via letter to these biospecimens for his “studies in gonorrhea related to the possible intra‐cellular location of the gonoccus [sic], the durcrey bacillus and the treponema pallidum as affecting response to therapy.” 1 Ashburn responded to Thayer's request by providing 8 biospecimens stored in paraffin (one specimen had been misplaced) from the NIH biorepository, in addition to related medical records to help “put the single tissue in perspective.” 1 , 40 It is unclear from Thayer's UNC VDEL records whether he ever used these Guatemalan tissue samples for his own experiments.

Policy Implications for Contemporary Biospecimen Research

Just as it was in Cutler's time, use of biospecimens and related data remains a critical component of current medical research. Programs such as the Precision Medicine Initiative, which promise individually tailored therapies, require vast amounts of data and health information from hundreds of thousands of people in order to advance medical science. 41 The banking of biospecimens and data for future research has become almost as important as conventional clinical trials and provides a springboard for thousands of secondary research protocols. 20 Despite the value of human biospecimens, however, our ethical and regulatory response to their use has struggled to keep up with the public's normative expectations.

Debate Over Use of Cadavers, Biospecimens, and Unethically Obtained Data

Infamous crimes committed by the Nazis under the guise of medical research provide another classic example of egregious experimentation clearly in violation of research ethics standards at the time. 42 The actions of the physician researchers involved were publicly condemned in the subsequent “Nazi Doctors Trial,” in which 16 defendants were found guilty of murder and torture and 7 were sentenced to death. 42 Although the opening statement for the prosecution argued at trial that the Nazi experiments “revealed nothing which civilized medicine can use,” 43 cadavers, biospecimens, and data from the Nazi era have in fact been integrated into ongoing medical education and scientific research for decades. 44 For example, Tubingen Medical School received 1,077 cadavers from a Holocaust execution site and, along with other West German medical schools, used skeletons and biospecimens from Holocaust victims in anatomy classes until the 1990s. 45 However, after public outcry in Israel and elsewhere over the continued use of these biospecimens and cadavers, “[t]he pendulum swung from retention to disposal,” and many anatomical specimens were given a religious burial. 44 , 45

It is worth clarifying the distinction between using artifacts, data, and specimens to educate people about past atrocities, to honor the victims, and to attempt to prevent similar occurrences versus using them for general medical or science education or ongoing research purposes. On one end of the spectrum, the use of unethically obtained Holocaust cadavers or biospecimens for ongoing research purposes is inappropriate because it uses the victims as a means to scientific ends and can be considered a re‐victimization. 46 For example, the use of Nazi victim cadavers and biospecimens by West German medical schools for general anatomy education is inappropriate, because by treating them similarly to those obtained via legitimate means (eg, donation after natural death), it fails to acknowledge in any way the indignity, exploitation, and pain that the victims experienced. The use of de‐identified data to advance future scientific research, such as those gathered by the Nazis during torturous hypothermia experiments, has also been controversial. 46

The other end of the spectrum involves using data, biospecimens, or other artifacts for education about the unethical event itself. For example, museums like the one at Auschwitz‐Birkenau display collections of shoes, hair, personal possessions, and art to “bear testimony” to the atrocities that occurred there. 47 Similarly, in 2012, the Bioethics Commission released its Guatemala Subject Data Spreadsheet of the de‐identified medical and experimental records of the Guatemala STD victims on its website along with its report. 6 These data were released for ethical and educational use to help “researchers and bio‐ethicists better understand the exploitation of some research subjects in the past to protect the contribution of all research participants in the future.” 48

US Human Subjects Research Regulations

Despite this agreement regarding use of biological samples derived during the Holocaust, the normative debate over appropriate standards of consent for general secondary research use of biospecimens is ongoing. In January 2017, the Department of Health and Human Services and other major stakeholders released the first comprehensive update to the US human subjects research regulations’ “Common Rule” since its codification in 1991. 18 These revisions grew out of an almost 6‐year process, which is still ongoing, 49 with one of the major points of controversy being informed consent to biospecimen research. 20

Under the original Common Rule conceptualization, informed consent and Institutional Review Board approval are required for federally funded research involving a living individual from whom the research obtains data or specimens via “intervention or interaction” or “identifiable private information.” 50 This means that while researchers can currently experiment with human biospecimens without consent, as long as they are de‐identified, they cannot do research with data or specimens readily associated with personal identifiers without consent or waiver. The Notice of Proposed Rulemaking (NPRM) for the regulatory revisions, which gave interested parties a legally required notice and comment opportunity, proposed changing the definition such that research with all biospecimens (whether they included “identifiable private information” or not) would trigger informed consent requirements, so as to “acknowledge and give appropriate weight to this distinct autonomy interest in research using biospecimens.…” 51 (p53942) A previous iteration of this notice, the Advance Notice of Proposed Rulemaking (ANPRM), cited the popular nonfiction book about secondary research on clinical biospecimens without consent— The Immortal Life of Henrietta Lacks —as highlighting these underpinning concerns. 52 (p44524) The ANPRM had originally posed the question of whether existing collections of biospecimens should be “grandfathered in” so that any new rule requiring consent for all biospecimens would not apply to them, 52 but as the final rule did not require informed consent for de‐identified biospecimens, the question became moot. 18

In addition to these debates in federal law, US case law protecting human biospecimens is scarce and is largely focused on the property interests such specimens might represent rather than the privacy and dignitary harms at the forefront of current debate. 53 , 54 , 55 Empirical data have demonstrated that while research participants are willing to donate biospecimens and data, there is disagreement over how much control contributors should retain over the specific purposes for which their specimens are used. 56

Moving Forward

Curators of contemporary biorepositories are grappling with the challenge of responding in ethically appropriate ways to these evolving normative public and professional standards. 57 On one hand, many commentators critiquing the proposed revisions to the Common Rule noted major practical limitations and great losses to the research community if biospecimens were required to be destroyed retroactively. 18 On the other hand, indefinitely archiving human biospecimens collected under egregious circumstances such as the Tuskegee and Guatemala experiments raises concerns.

As was the case for the Nazi medical experiments, the consensus is that—under professional research norms at the time of collection —material gathered during the Guatemala and Tuskegee experiments was done so unethically. 4 (p93), 19 These experiments were a gross violation of the subjects’ autonomy interests as well as social justice considerations and caused profound and indefinite harm that continues to engender anger, fear, and mistrust among affected communities. 58 , 59

Whether or not the Guatemala or Tuskegee biospecimens still exist in government archives is not a matter of public knowledge, although it appears likely that they do. For example, in 2008, the senior advisor for laboratory science for the Coordinating Center for Infectious Diseases at the CDC testified before the US House of Representatives that the CDC's archived biospecimens are only destroyed in “extremely rare circumstances,” such as “when required by an Institutional Review Board.” 60 The majority of CDC laboratories have no uniform destruction protocols in place, although destruction occurs only “after study and consultation and in a very controlled and documented manner.” 60 In addition, after a vial of live smallpox virus was found in an unsecure storage room at the NIH in July 2014, 61 all US government departments and agencies that work with infectious agents were urged to conduct a “safety stand‐down” to ensure laboratory safety practices. 62 As part of this procedure, the CDC searched 1,000 of its own laboratory rooms and inventoried and documented over 8 million stored samples. 62

However, an initial search requested by the authors 63 and conducted by the CDC's Agency for Toxic Substances and Disease Registry failed to turn up any record regarding biospecimens collected during the Tuskegee or Guatemala studies—or even any documents that apply to the “reevaluation, review, retention, or destruction” of any such specimens. 64 Given the plethora of public government documentation available regarding PHS involvement in both studies and the retention and discussion of the specimens they generated, 4 , 17 , 19 a more thorough public accounting of whether or not these biospecimens are still in the possession of the US government as well as their current location is warranted. If these biospecimens still exist, they should be retired from the government's biorepositories and their disposition determined by independent stakeholders—including representatives of the communities from which they were obtained. As was the case for the Nazi medical experiment specimens, destruction is one possibility. Other options include donation to a museum to represent the physical remains and sacrifices of the victims, much like the human hair on display at the Auschwitz‐Birkenau Museum. 47

One counterargument to this call for retiring the specimens is that access for secondary research use honors the victims. “The suffering is done—let someone benefit from all the pain,” argued Lucien A. Ballin, who helped publicize data from Nazi hypothermia experiments at the Dachau concentration camp. 65 However, we believe that this line of reasoning—while perhaps appropriate for anonymous data 66 or research ethics pedagogy 48 —does not apply to biospecimens (either identified or de‐identified) in research biorepositories. It became clear in the recent debate over the human subjects research regulations that some members of the public believe that de‐identified biospecimens have a different normative value than do data. People ascribe a higher sense of identity and ownership to biospecimens that is ethically compelling on the basis of respect for persons as well as encouraging trust in the research enterprise. Moreover, while the US Bioethics Commission did not release any identifying information about victims of the Guatemala experiments, the government of Guatemala released identified medical information and some photographs. 9 , 10 , 11 Therefore, some victims may be readily identifiable.

Ultimately, the federal government declined to regulate research with de‐identified human biospecimens as some advocates had demanded under the recent revisions to the rules. Whether or not this was the correct balance to strike between the protection of participant autonomy and public beneficence and justice, many parties came away from the compromise disappointed. Retirement of the Tuskegee and Guatemala biospecimens would be a worthy response to some of the ongoing criticisms of continued research use of biospecimens. It would also constitute a clear acknowledgment of the reprehensible nature of the Tuskegee syphilis and Guatemala intentional exposure experiments.

While the Guatemala STD intentional exposure experiments occurred over only a 2‐year period, biospecimens collected during these and the diagnostic methodology experiments remained part of US research protocols for at least a decade following the completion of the original research. These biospecimens, along with the Tuskegee samples, became part of a critical federal biorepository of syphilitic blood and tissue used for research for both public health and business purposes. Though the appropriate research use of biospecimens is still a matter of debate, ethicists have roundly condemned the continued use of cadavers and specimens obtained during the Holocaust. We call as well for the retirement of any biospecimens collected from the Guatemala and Tuskegee experiments still in existence in federal biorepositories today.

Funding/Support

Kayte Spector‐Bagdady receives ongoing support from the Center for Bioethics and Social Sciences in Medicine at the University of Michigan Medical School.

Conflict of Interest Disclosures : Both authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest. Kayte Spector‐Bagdady was an employee of the Presidential Commission for the Study of Bioethical Issues from 2010 to 2015. During that time she was a staff lead on the commission's report on the Guatemala STD experiments. Paul Lombardo was a paid senior advisor to the commission from 2011 to 2016, during which time he also worked on the report on the Guatemala STD experiments.

Acknowledgments : The authors would like to thank Olivia Deich, MPH; Karen Meagher, PhD; Jason L. Schwartz, PhD; and Andrew G. Shuman, MD, for their insights and comments.

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• Copy URL https://www.pbs.org/newshour/health/us-apologizes-for-60-year-old-unethical-syphilis-study-in-guatemala

U.S. Apologizes for ‘Reprehensible’ 1940s Syphilis Study in Guatemala

U.S. officials apologized Friday for unethical medical experiments conducted in Guatemala more than 60 years ago, in which prison inmates were deliberately infected with syphilis.

The experiments were conducted between 1946 and 1948 by Dr. John C. Cutler, a U.S. public health service doctor who was also involved in the infamous Tuskegee syphilis study in the United States.

Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius issued a joint statement apologizing for the experiments:

“The sexually transmitted disease inoculation study conducted from 1946-1948 in Guatemala was clearly unethical. Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices.”

The history of the Guatemala study was uncovered by Wellesley College professor Susan Reverby, a medical historian who has written two books about the Tuskegee case, in which black men with syphilis were observed — but not treated — by U.S. government researchers for nearly 40 years. Reverby was reading Cutler’s papers in an archive at the University of Pittsburgh, looking for references to the Tuskegee study, when she came across descriptions of the experiments in Guatemala.

“So I started to read it, and I said, ‘Oh my god,'” Reverby says.

In the study, the researchers were investigating whether penicillin — which was already being used to treat syphilis — could prevent the disease if it was administered right after someone was exposed to the bacteria.

The researchers exposed hundreds of people in Guatemala to the disease. Many were men who were prison inmates, others were residents of an army barracks and mental hospital. None of the subjects were asked for their consent. The researchers used visits with prostitutes who were infected with syphilis to expose the men to the disease (such visits were legal in Guatemala at the time). They also, Reverby writes, “used direct inoculations made from syphilis bacteria poured into the men’s penises and on forearms and faces that were slightly abraded when the ‘normal exposure’ produced little disease.”

They did treat the people with penicillin afterwards, but, Reverby writes, it’s not clear whether everyone was cured, or even whether they received what would have been considered adequate treatment.

The Guatemala experiment differed from the Tuskegee case, Reverby says, because people were actually exposed to the disease and then treated, instead of being denied access to treatment for a disease that they already had, as happened in the Tuskegee case.

Even within the context of the much more lax research ethics standards of the time, Reverby says, the research “fell off the edge” of what was acceptable.

“Even within the context of history, this was something they shouldn’t have been doing — and they knew that,” Reverby said. In fact, she cites a letter in which Surgeon General Thomas Parran said “You know, we couldn’t do such an experiment in this country.”

Reverby presented her findings at a medical history association meeting in May, and also wrote them up for publication — they’ll be published in January in the Journal of Policy History, but a pre-publication version of the four-page paper is available on Reverby’s website.

The government got involved in the spring, when Reverby showed the paper to David Sencer, a retired director at the Centers for Disease Control and Prevention whom she knew from her research on the Tuskegee experiment’s history. Sencer passed it on to current CDC officials, and the agency sent a syphilis specialist to examine the papers in the University of Pittsburgh archive. That specialist confirmed the accuracy of Reverby’s report.

Now, the government, in addition to issuing its apology, will also convene a panel of independent experts through the National Academies of Sciences Institute of Medicine to conduct a fact-finding probe of the events in Guatemala.

And Sofia Porres, of the Guatemalan Embassy, told the Washington Post that the Guatemalan government would also investigate. “We of course are very upset about this, and we think it’s a very unfortunate event,” she said. “We’re going to do an investigation as well to see if there are any survivors, family, etc.”

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U.S. Government Study in 1940s Guatemala

Johns Hopkins welcomes bioethical inquiry into the U.S. government's Guatemala study from the 1940s and its legacy. For more than half a century since the time of that study, scholars and ethicists have worked with government officials to establish rigorous ethical standards for human research. On this page, please find:

• Information about a lawsuit filed in 2015 against Johns Hopkins, the Rockefeller Foundation and Bristol-Myers Squibb Company regarding the Guatemala study from the 1940s.
• A Johns Hopkins commentary posted in 2012 about the Guatemala study from the 1940s.
• Additional information and resources on this topic and on today’s guiding principles of institutional review boards for research involving human subjects.

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Johns hopkins media statement - april 1, 2015.

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Johns Hopkins expresses profound sympathy for individuals and families impacted by the deplorable 1940s syphilis study conducted by the U.S. government in Guatemala. This was not a Johns Hopkins study. Johns Hopkins did not initiate, pay for, direct or conduct the study in Guatemala. No nonprofit university or hospital has ever been held liable for a study conducted by the U.S. government.  It has been well established by a Presidential Commission that this unconscionable research was funded and executed by the United States government. The President, U.S. Secretary of State and U.S. Secretary of Health and Human Services have apologized to the Guatemalan government and to all affected. The plaintiffs’ essential claim in this case is that prominent Johns Hopkins faculty members’ participation on a government committee that reviewed funding applications was tantamount to conducting the research itself and that therefore Johns Hopkins should be held liable. Neither assertion is true. A class action lawsuit seeking to hold federal officials responsible for the Guatemala study has been filed and dismissed. U.S. District Court Judge Reggie Walton dismissed that action in 2012 and stated that the pleas of victims for relief are more appropriately directed to the political branches of the federal government. For more than half a century since the time of the Guatemala study, scholars, ethicists and clinicians have worked with government officials to establish rigorous ethical standards for human research. Johns Hopkins welcomes bioethical inquiry into the U.S. government's Guatemala study and its legacy. This lawsuit, however, is an attempt by plaintiffs’ counsel to exploit a historic tragedy for monetary gain. Plaintiffs’ legal claims are not supported by the facts. We will vigorously defend the lawsuit.

A Letter to the Johns Hopkins Community - April 1, 2015

SUBJECT : Challenges from the past Dear Member of the Johns Hopkins Community, More than 60 years ago, the U.S. government conducted an unconscionable and unethical experiment in Guatemala, in which U.S. government researchers deliberately infected vulnerable citizens of Guatemala with syphilis and other infectious diseases. We feel profound sympathy for the individuals and families impacted by this deplorable study. When the details of this study came to light, a Presidential Commission determined that the Guatemala Study was funded and conducted by the United States government. In 2010, the President of the United States, the Secretary of State and the Secretary of Health and Human Services apologized to all affected. In 2012, a federal district court concluded that the pleas of victims for relief are more appropriately directed to the political branches of the federal government. Today, attorneys representing Guatemalan plaintiffs announced that they are suing The Johns Hopkins University and Johns Hopkins Health System, alleging that Johns Hopkins was responsible for the study. The plaintiffs’ essential claim in this case is that prominent Johns Hopkins faculty members’ participation on a government committee that reviewed funding applications was tantamount to conducting the research itself, and therefore that Johns Hopkins should be held liable.  Neither assertion is true. This was not a Johns Hopkins study. Johns Hopkins did not initiate, pay for, direct or conduct the study in Guatemala. Participation in the review of government research was then and is today separate from being a Johns Hopkins employee, and no nonprofit university or hospital has ever been held liable for a study conducted by the U.S. government.  As a leading global research university, Johns Hopkins values rigorous and open scrutiny of history, even when it is complex and uncomfortable. We know that historians have previously linked prominent Johns Hopkins faculty members in various ways to other unethical government research studies in Tuskegee and Terre Haute. Although separate from the Guatemala lawsuit, these studies were all deplorable and all demand reflection upon the broader legacy of unethical research. It is important to confront and learn from the past.  At the same time, we cannot let unfounded allegations go unchallenged. We will defend the institution vigorously in court against legal responsibility for the government’s Guatemala study. If you would like more information about the university’s position on the lawsuit, we have released a media statement that you can find here, along with information about the Presidential Commission on the research in Guatemala and its findings. Sincerely, Ronald J. Daniels President, The Johns Hopkins University Paul B. Rothman, M.D. Dean of the Medical Faculty CEO, Johns Hopkins Medicine Michael J. Klag, M.D., M.P.H. Dean, Johns Hopkins Bloomberg School of Public Health

A Commentary on Reports by the Presidential Commission for the Study of Bioethical Issues - June 19, 2012

Additional information and resources.

• Presidential Commission Report -  Institutional Review Boards at Johns Hopkins Medicine
• Presidential Commission Report -  Moral Science: Protecting Participants in Human Subjects Research
• Institutional Review Boards at Johns Hopkins Medicine
• The Infamous Syphilis Study and Its Legacy Examining Tuskegee (Susan M. Reverby ed., 2009)
• Reverby, S. (2015, April 3). Suing for Justice? More on the U.S. STD Studies in Guatemala. Retrieved from  http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=7365&blogid=140Bioethics

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Guiding Principles of Institutional Review Boards (IRB)

Johns Hopkins experts discuss the guiding principles of Institutional Review Boards in research involving human subjects respect for persons, risk and benefit analysis, and justice and fairness.

"Ethically Impossible" STD Research in Guatemala from 1946 to 1948

Following the revelation last fall that the PHS supported research on sexually transmitted diseases in Guatemala from 1946 to 1948, President Obama asked the Bioethics Commission to oversee a thorough fact-finding investigation into the studies. Commission staff carefully reviewed more than 125,000 original pages of documents and approximately 550 secondary sources collected from public and private archives around the country. Commission staff also completed a fact finding trip to Guatemala and met with Guatemala’s own internal investigation committee.

The PHS research involved intentionally exposing and infecting vulnerable populations to sexually transmitted diseases without the subjects’ consent. “In the Commission’s view, the Guatemala experiments involved unconscionable basic violations of ethics, even as judged against the researchers’ own recognition of the requirements of the medical ethics of the day,” Commission Chair Amy Gutmann, Ph.D., said. “The individuals who approved, conducted, facilitated and funded these experiments are morally culpable to various degrees for these wrongs.”

The full report, " Ethically Impossible" STD Research in Guatemala from 1946 to 1948,  also includes the Commission’s ethical analysis of the case.

• Read   "Ethically Impossible" STD Research in Guatemala from 1946 to 1948  report with links to historical documents
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• Read the charge from the President
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First, do no harm: the US sexually transmitted disease experiments in Guatemala

Affiliation.

• 1 Michael A. Rodriguez is with the Blum Center on Poverty and Health in Latin America and the Department of Family Medicine, David Geffen School of Medicine, University of California, Los Angeles. Robert García is with The City Project, Los Angeles.
• PMID: 24134370
• PMCID: PMC3828982
• DOI: 10.2105/AJPH.2013.301520

Beginning in 1946, the United States government immorally and unethically-and, arguably, illegally-engaged in research experiments in which more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases. Many have been left untreated to the present day. Although US President Barack Obama apologized in 2010, and although the US Presidential Commission for the Study of Bioethical Issues found the Guatemalan experiments morally wrong, little if anything has been done to compensate the victims and their families. We explore the backdrop for this unethical medical research and violation of human rights and call for steps the United States should take to provide relief and compensation to Guatemala and its people.

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• Published: 08 February 2012

Human experiments: First, do harm

• Matthew Walter 1  

Nature volume  482 ,  pages 148–152 ( 2012 ) Cite this article

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In the 1940s, US doctors deliberately infected thousands of Guatemalans with venereal diseases. The wound is still raw.

The injections came without warning or explanation. As a low-ranking soldier in the Guatemalan army in 1948, Federico Ramos was preparing for weekend leave one Friday when he was ordered to report to a clinic run by US doctors.

Ramos walked to the medical station, where he was given an injection in his right arm and told to return for another after his leave. As compensation, Ramos's commanding officer gave him a few coins to spend on prostitutes. The same thing happened several times during the early months of Ramos's two years of military service. He believes that the doctors were deliberately infecting him with venereal disease.

Now 87 years old, Ramos says that he has suffered for most of his life from the effects of those injections. After leaving the army, he returned to his family's remote village, on a steep mountain slope northeast of Guatemala City. Even today, Las Escaleras has no electricity or easy access to medical attention. It wasn't until he was 40, nearly two decades after the injections, that Ramos saw a doctor and was diagnosed with syphilis and gonorrhoea. He couldn't pay for medication.

“For a lack of resources, I was here, trying to cure myself,” says Ramos. “Thanks to God, I would feel some relief one year, but it would come back.” Over the decades, he has endured bouts of pain and bleeding while urinating, and he passed the infection onto his wife and his children, he told Nature last month in an interview at his home.

Ramos's son, Benjamin, says that he has endured lifelong symptoms, such as irritation in his genitals, and that his sister was born with cankers on her head, which led to hair loss. Ramos and his children blame the United States for their decades of suffering from venereal disease. “This was an American experiment to see if it caused harm to human beings,” says Benjamin.

Ramos is one of a handful of survivors from US experiments on ways to control sexually transmitted diseases (STDs) that ran in semi-secrecy in Guatemala from July 1946 to December 1948. US government researchers and their Guatemalan colleagues experimented without consent on more than 5,000 Guatemalan soldiers, prisoners, people with psychiatric disorders, orphans and prostitutes. The investigators exposed 1,308 adults to syphilis, gonorrhoea or chancroid, in some cases using prostitutes to infect prisoners and soldiers. After the experiments were uncovered in 2010, Ramos and others sued the US government, and US President Barack Obama issued a formal apology. Obama also asked a panel of bioethics advisers to investigate, and to determine whether current standards adequately protect participants in clinical research supported by the US government.

When details of the Guatemalan experiments came to light, US health officials condemned them as 'repugnant' and 'abhorrent'. Last September, the Presidential Commission for the Study of Bioethical Issues went further, concluding in its report 1 , that “the Guatemala experiments involved unconscionable violations of ethics, even as judged against the researchers' own understanding of the practices and requirements of medical ethics of the day” (see 'Evolving ethics').

Yet that report and documents written by the researchers involved in the Guatemalan work paint a more complex picture. John Cutler, the young investigator who led the Guatemalan experiments, had the full backing of US health officials, including the surgeon general.

“Cutler thought that what he was doing was really important, and he wasn't some lone gunman,” says Susan Reverby, a historian at Wellesley College in Massachusetts, whose discovery of Cutler's unpublished reports on the experiments led to the public disclosure of the research 2 .

Cutler and his superiors knew that some parts of society would not approve. But they viewed the studies as ethically defensible because they believed that the results would have widespread benefits and help Guatemala to improve its public-health system. Those rationalizations serve as a warning about the potential for medical abuses today, as Western clinical trials increasingly move to developing countries to take advantage of lower costs and large populations of people with untreated disease. Bioethicists worry that laxer regulations and looser ethical standards in some countries allow researchers to conduct trials that would not be allowed at home. “The strongest lesson should be that the same rules, same principles, same ethics should apply no matter where you are,” says Christine Grady, acting chief of the Department of Bioethics at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland, and a member of the bioethics commission.

The war against syphilis

In the early decades of the twentieth century, US health officials were consumed by the battle against STDs, much as subsequent generations of researchers have fought cancer and HIV. In 1943, Joseph Moore, then chairman of the US National Research Council's Subcommittee on Venereal Diseases, estimated that the military would face 350,000 new infections of gonorrhoea annually, “the equivalent of putting out of action for a full year the entire strength of two full armored divisions or of ten aircraft carriers”. The government launched vigorous campaigns of research, treatment and advertising to combat the problem. “She may look clean — but pick-ups, 'good time' girls, prostitutes spread syphilis and gonorrhea”, read one poster issued by the US Public Health Service, which promotes health initiatives and medical research.

Many of the country's leading health officials were veterans of that fight. The surgeon general who would approve the proposal for the Guatemalan experiments, Thomas Parran, had previously run the Public Health Service's Venereal Disease Research Lab (VDRL) in New York, and had written two books on the topic. And the associate director of that lab went on to serve as the chief of the research grants office at the NIH, which would fund the Guatemalan work in early 1946.

“You had a very active venereal-disease division,” says John Parascandola, a former historian of the Public Health Service and author of Sex, Sin and Science: A History of Syphilis in America (Praeger, 2008). Even after researchers demonstrated in 1943 that penicillin was an effective treatment for syphilis and gonorrhoea, they had many questions about preventing and treating those diseases and others. “You still had all these people who cut their teeth with venereal diseases and were interested in that topic. Certainly, the venereal-disease division in the 1940s didn't think the problem was licked.”

The military, in particular, wanted to develop prophylactic techniques better than the 'pro kit' that had been in use for decades. After sex, servicemen were supposed to inject a solution containing silver into their penises to prevent gonorrhoea, and rub a calomel ointment over their genitals to prevent syphilis. The methods were painful, messy and not very effective.

To test treatments and prophylaxis, the Public Health Service had argued in late 1942 that it was crucial to give the disease to people under controlled conditions. Officials debated the legality and ethics of this, and even solicited the input of the US attorney general. They decided to do the work at a federal prison in Terre Haute, Indiana, using volunteer inmates.

Cutler was one of the doctors charged with carrying out the work. When the prison study began in September 1943, Cutler was 28, and had finished medical school only two years before. The researchers tried to infect prisoners by depositing bacteria — sometimes gathered from prostitutes arrested by the Terre Haute police — directly on the end of the penis. The experiment established several practices that Cutler would go on to use in Guatemala, including working with local law-enforcement agencies and prostitutes. But the researchers could not develop a means to effectively infect people — a necessary step towards testing prophylactic techniques. Within ten months, the experiments were abandoned.

Captive population

After Terre Haute, researchers began to plan a more ambitious study. They wanted to try causing infections through what they called normal exposure, in which people would have sex with infected prostitutes.

In 1945, a Guatemalan health official who was working for a year at the VDRL offered to host studies in his country. As director of the Guatemalan Venereal Disease Control Department, Juan Funes was uniquely positioned to help. Prostitution was legal in his country at the time, and sex workers were required to visit a clinic twice a week for examinations and treatment. Funes oversaw one of the main clinics, so he could recommend infected prostitutes for experiments. Cutler and other scientists at the VDRL were quickly sold on the idea: they proposed a programme, which was approved with a budget of US$110,450.

According to a Guatemalan report 3 , the US plan was a clear violation of contemporary Guatemalan law, which made it illegal to knowingly spread venereal diseases. But the country was experiencing political upheaval in the mid-1940s and the bureaucracy did not object to the US plan. Government officials as high up as Luis Galich, head of the Guatemalan ministry of public health, were involved in the US study, and even President Juan José Arévalo, who had been elected in 1945, was at least aware of a syphilis experiment being done by US scientists. The study presented a chance to tap into US funding to upgrade Guatemala's inadequate public-health infrastructure, and to import scientific expertise.

Cutler arrived in the country in August 1946 and began setting up experiments. He planned to assess diagnostic blood tests, and to determine the effectiveness of penicillin and an agent called orvus-mapharsen in preventing STDs. At first, Cutler tried using infected prostitutes to spread gonorrhoea to soldiers: he and his team used various bacterial strains to inoculate sex workers, who then had intercourse with many men. Records show that one prostitute had sex with 8 soldiers in a period of 71 minutes. The team also carried out similar experiments using sex workers at a prison.

But it was hard to induce infections by the 'natural' method. So researchers turned to inoculation, swabbing the urethra with an infected solution, or using a toothpick to insert the swab deep into the urethra. At the National Psychiatric Hospital of Guatemala, scientists scratched male patients' penises before artificial exposure to improve infection rates, and injected syphilis into the spinal fluid of seven female patients.

According to the US bioethics commission's report, Cutler's team exposed 558 soldiers, 486 patients at the psychiatric hospital, 219 prisoners, 6 prostitutes and 39 other people to gonorrhoea, syphilis or chancroid. But the commission was unable to determine how many people actually developed infections or how many of the participants were treated. Researchers also measured the accuracy of diagnostic tests in experiments that involved orphans and people with leprosy, as well as people from the psychiatric hospital, prison and the army.

The commission says there is no evidence that Cutler sought or obtained consent from participants, although in some cases he did get permission from commanding officers, prison officials and doctors who oversaw the patients at the psychiatric hospital. In a letter to his supervisor, John Mahoney, director of the VDRL, Cutler openly admits to deceiving patients at the psychiatric hospital, whom he was injecting with syphilis and later treating. “This double talk keeps me hopping,” Cutler wrote.

Cutler and his colleagues treated some people brutally. In one case, detailed by the bioethics commission, the US doctors infected a woman named Berta, a patient at the psychiatric hospital, with syphilis, but did not treat her for three months. Her health worsened, and within another three months Cutler reported that she seemed close to death. He re-infected Berta with syphilis, and inserted pus from someone with gonorrhoea into her eyes, urethra and rectum. Over several days, pus developed in Berta's eyes, she started bleeding from her urethra and then she died.

Yet Cutler did do some good in Guatemala. He took steps to improve public health, initiating a venereal-disease treatment programme at the military hospital and developing a prophylactic plan for the army. He treated orphans for malaria, lobbied his supervisors to supply the army with penicillin — he was turned down — and trained local doctors and technicians. And he provided treatment for 142 people who may have had venereal disease but had not been exposed to it as part of the research.

At the prison, he reported that “we have found a very ready acceptance of our group, both on the part of the prison officials and the part of the inmates, which we think stems from the fact that we now have given them a program of care for venereal disease, which they have lacked in the past. Thus we feel that our treatment program is worthwhile and fully justified.”

In the end, Cutler could claim no real success in his experiments, in part because he was never able to infect people reliably without resorting to extreme methods. He secured an extension to continue the experiments from June to December 1948, and he left Guatemala at the end of that year. Other researchers published some of the blood-test results, but Cutler did not publish his work on prophylactic methods. The experiments were not only unconscionable violations of ethics, the bioethics commission charges, they were also poorly conceived and executed.

A distinguished career

Despite the failures, the work burnished Cutler's credentials. A few months after he arrived home, the World Health Organization sent Cutler to India to lead a team demonstrating how to diagnose and treat venereal diseases. In the 1960s, he became a lead researcher in the infamous Tuskegee experiment in Alabama, in which hundreds of black men with syphilis were studied for decades without receiving treatment. He flourished in the Public Health Service and later became a professor of international health at the University of Pittsburgh in Pennsylvania. He died in 2003, well before details of the Guatemala experiments were exposed.

Michael Utidjian was an epidemiologist at Pittsburgh in the late 1960s and co-authored two papers with Cutler. He describes his former colleague as devoted to venereal-disease studies and enthusiastic about international research. “He did some pioneer work out in India using penicillin to treat the commoner STDs.” But Utidjian says that Cutler was a flawed researcher. “I wouldn't rank him as a top-flight scientist or designer of studies.” The two scientists collaborated on a study to test the effectiveness of a topical prophylaxis in prostitutes at a brothel in Nevada. However, the poor implementation of the experiment led to “pretty worthless” results, says Utidjian.

The participants in Cutler's Guatemalan study fared far worse than the doctor himself. Shuffling among the tin-roofed homes in Las Escaleras, Ramos is bone thin and speaks in a mumble, made worse by his lack of teeth. He says that he put off treatment until about ten years ago, when it became too painful to urinate. His son rushed him to a hospital, where doctors inserted a catheter and later performed an operation.

Gonzalo Ramirez Tista lives in the same village as Ramos and says that his father, Celso Ramirez Reyes, also participated in the experiments during his three years in the army. He was required by the scientists to have sex with infected prostitutes. “They gave him an order, and it came from a superior,” says Tista. They also gave him injections, and within days he noticed pus coming out of his penis. “He still had these symptoms when he left [the military], and he infected my mother.” After his service, gonorrhoea left Reyes with sores, poor eyesight and lethargy.

Like Ramos's family, Tista is a party to the lawsuit seeking compensation from the US government. Neither man could provide documents to support their claims. But Pablo Werner, a doctor with Guatemala's Human Rights Ombudsman's office, has reviewed the cases and found that Ramos's and Reyes's stories are supported by the timing of their military service and details in the medical histories that they gave. Reyes is also named in a database of research participants that was compiled by Guatemala's National Police Historical Archive from Cutler's papers.

Never again

The US Department of Justice requested last month that the compensation case be dismissed, arguing that the courts are not the “proper forum” for it. But last September, a panel of the presidential bioethics commission recommended 4 that the government set up a general compensation system for test participants harmed by federally funded research.

This January, the US Department of Health and Human Services committed nearly $1.8 million to improving the treatment of STDs in Guatemala and strengthening ethics training there regarding research on humans. The plaintiffs are not satisfied and intend to press their case, says Piper Hendricks, an international human-rights lawyer with Conrad & Scherer in Fort Lauderdale, Florida, who is representing them.

As the case moves forward, researchers are wrestling with how to judge the actions of Cutler's team, and how to prevent such abuses from happening again. The bioethics commission argues that Cutler and his superiors knew that they were violating the medical ethics of their day, because they had sought the consent of participants in Terre Haute. And in Guatemala, the researchers took steps to suppress knowledge of their work. One colleague told Cutler that the US surgeon general “is very much interested in the project and a merry twinkle came into his eye when he said, 'You know, we couldn't do such an experiment in this country'.”

But the ethical landscape was evolving rapidly at the time. The standards of the 1940s were “a lot murkier” than those of today, says Susan Lederer, a bioethicist at the University of Wisconsin–Madison. “The idea that it was so clear in 1946 to me doesn't ring true.”

In late 1946, after Cutler had started his work in Guatemala, 23 Nazi doctors and officials went on trial in Nuremberg, Germany, for the inhuman experiments that they had carried out in concentration camps during the Second World War. From that trial emerged the Nuremberg Code, a set of principles that mandated that experimenters obtain voluntary consent from participants, that participants be capable of giving such consent and that experiments avoid unnecessary physical and mental harm.

Although such tight standards were not entirely foreign to researchers before the Nuremberg trials, few followed them. In 1935, for example, the Supreme Court of Michigan stated that researchers could get consent from caregivers of participants, which Cutler did in a sense when he consulted commanding officers and other officials. Many of Cutler's participants were poor, uneducated people from indigenous populations, whom the scientists viewed as incapable of understanding the experiments.

At the time, some of the United States's top researchers worked without obtaining consent from individuals. Jonas Salk, who later earned fame for developing the polio vaccine, and Thomas Francis Jr, a leading influenza researcher, intentionally infected patients at a psychiatric hospital in Ypsilanti, Michigan, with influenza in 1943 (ref. 5 ). There is evidence that the patients did not all consent to the experiments.

Cutler and his superiors apparently thought it was acceptable in Guatemala to cross ethical lines that they would not have breached at home — an issue that raises concern today, with Western companies increasingly running clinical trials in foreign countries, particularly in developing nations. In 2010, the US Department of Health and Human Services investigated all requests by companies to market their drugs in the United States, and found that in 2008, nearly 80% of approved applications used data from clinical trials in other countries.

Developing nations often have lower medical standards than developed countries, and can't enforce rules as effectively. In India, for example, human-rights activists and members of parliament say that foreign drug companies often test experimental drugs on poor, illiterate people without obtaining their consent or properly explaining the risks.

And in 2009, the pharmaceutical giant Pfizer agreed to pay up to $75 million to settle lawsuits over the deaths of Nigerian children who had participated in tests of an experimental antibiotic. Nigerian officials and activists had claimed that the company had acted improperly by, for example, not obtaining proper authorization or consent. But Pfizer denies the allegations and did not admit any wrongdoing in the settlement.

Ethicists also warn about practices viewed as acceptable today, such as testing medications on patients who are extremely ill, and who see new treatments as their only hope, no matter how dangerous they are. Lederer notes that some trials of cancer drugs involve particularly toxic compounds. In the future, she says, “people might say, 'how can people who are so sick make informed decisions?'”

For Grady, the lessons from Guatemala are fundamental tenets of bioethics: not every method is acceptable, transparency is key and scientists should remember that they are working with human beings.

But in clinical research, she says, the ethical lines aren't always well defined. “When you get to the details of what that means in a particular case, people disagree.” And that may be the most troubling lesson of the Guatemalan experiments. In any era, many if not most researchers might agree that a certain practice or rule is justified and necessary. But for later generations, the barbarism of the past seems only too obvious.

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Matthew Walter is a freelance writer in New York. Additional reporting provided by Richard Monastersky.,

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US bioethics panel urges stronger protections for human subjects 2011-Dec-15

A shocking discovery 2010-Oct-04

Blogpost: US seeks to dismiss lawsuit over unethical VD research in Guatemala

Blogpost: Guatemala experiments 'heinous', commission tells Obama

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Walter, M. Human experiments: First, do harm. Nature 482 , 148–152 (2012). https://doi.org/10.1038/482148a

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Published : 08 February 2012

Issue Date : 09 February 2012

DOI : https://doi.org/10.1038/482148a

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