Time line

While researching the Cutler archive at the University of Pittsburgh, Dr Reverby discovered documents which described the Guatemala enterprise. After performing an extensive review, she contacted Dr David Sencer, the former Director of the U.S. Centers for Disease Control and Prevention, who in turn contacted CDC officials. During the summer of 2010, the US Government recovered the Cutler documents from Pittsburgh and instituted a formal review, which included an initial review of the documents by a Centers for Disease Control (CDC) team. This work, although preliminary, clearly identified major ethical lapses in clinical research, and in October 2010, the US Government issued a formal apology to Guatemala.1 In 2010, the President directed the US Presidential Commission on Bioethical Issues to launch a comprehensive investigation which included public hearings, a review and compilation of all available documents, as well as searches through government and institutional archives for related papers.

This paper will provide an overview of the Cutler documents and experimental rationale for the Guatemala studies, and briefly describe the studies that were performed.

The Cutler documents

The Cutler documents include over 12 000 pages of original documents left at the University of Pittsburgh. These include experimental notebooks, cards on individual subjects, descriptions of experiments, as well as photographic documentation of the subjects who were in the studies. They also include extensive diagnostic and treatment histories for the individual subjects. In addition to the Cutler documents, the Bioethics Commission reviewed over 550 documents concluding 125 000 pages of additional material which was obtained through public health service archives. A database was developed of all the patient material which was in the archive, which at its conclusion, included over one million individual patient entries. These materials are all available online.8

Who was John Cutler?

Dr Cutler is an intriguing figure, and is clearly the centre of the issues in the investigation.2 In 1946, he was a 32-year-old US Public Health Service physician, and was clearly ambitious.

Besides the Guatemala studies, Dr Cutler was intimately involved with the Tuskegee studies of untreated syphilis.6 ,7 In later life, he was known as a progressive public health force. He was a major advocate of family planning, major advocate of Planned Parenthood (a large family planning organisation in the USA), worked in venereal disease control at the US Public Health Service, and later was the acting dean at the University Of Pittsburgh School Of Public Health. He had extensive involvement in providing family planning programmes in sub-Saharan Africa. He died in 2005 at the age of 87 years. Dr Cutler was consistently unapologetic about the Tuskegee studies. He never mentioned the Guatemala work in any known written or oral communications that have been uncovered.

The historical context of the Cutler experiments

By the end of World War II, the efficacy of penicillin for the treatment of syphilis and gonorrhoea was being elucidated. During the war, John Mahoney and his colleagues at the US Public Health Service Venereal Diseases Division had already published studies demonstrating that penicillin was effective for the treatment of syphilis.9 These findings were rapidly translated into clinical public health practice in the immediate post-war era (Figure 1) with the implementation of civilian rapid treatment centres for treatment of syphilis.

Syphilis and other sexually transmitted infections had tremendous impact on military deployability because of the prolonged treatment regimens that were required, as well as the high incidence rates of sexually transmitted infections in militarised areas. By contrast with the present conflicts, there was substantial interaction between US military forces and the local populations in Europe and Asia, and there were large programmes in place for venereal disease control. Although military public health practice did emphasise prevention and the use of condoms, little was known about the efficacy of post-exposure treatment and prophylaxis or the management of sexual contacts. For instance, the standard contemporary texts, such as Stokes’ Modern Clinical Syphilology,10 did not address any preventive or prophylactic treatment for any of the major venereal diseases.

Besides the issue of preventive treatment, there were also questions in the syphilology community on the role, if any, of acquired immunity. These questions included: ‘In patients with treated syphilis, is there any subsequent immunological protection from re-infection? Are patients with latent syphilis protected from primary re-infection?’

These questions were largely driven by military exigency. The primary objective was understanding whether a preventive treatment regimen be evaluated in a model where humans are infected under controlled conditions.

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Figure 1

WWII ‘Syphilis: a million new victims each’ poster. Copyright: The National Library of Medicine believes this item to be in the public domain.

Since the major diseases of interest, syphilis and gonorrhoea, had (and have) no animal model of either infection or transmissibility, the investigators faced the constraints of the need to develop an experimental human model. In order to understand and study the efficacy of prevention interventions, defining transmission efficiency became an initial objective.

Once an experimental model could be developed, the investigators were then interested in understanding the efficacy of various treatment regimens for preventive therapy. The major question was: ‘What were the effects of traditional arsenicals, such as orvus-mapharsen, compared to penicillin, which was clearly the emerging treatment of choice?’

Funding

Dr Cutler developed a grant proposal in collaboration with other PHS investigators and collaborators in Guatemala. The primary Guatemalan collaborating physician, Dr Juan Funes, had trained at the USPHS Venereal Disease Research Laboratory (VDRL) in Staten Island, and was interested in developing joint clinical studies. The overall objective was to provide more effective preventive tools for US personnel, who were potentially exposed to sexually transmitted infections. Also, unmentioned in any of their reports, but well known to historians, are the US military actions which were being undertaken in this area in the late 1940s in attempts to suppress a communist insurgency.

The Public Health Service study section, which approved these studies, and provided a US$146 000 grant in 1946 (equivalent to US$1.7 million now) included prominent individuals in venereal disease at the time including, Dr Thomas Turner, Dr Thomas Parran, Harry Eagle, John Stokes, Joseph Earle Moore, John Mahoney and Cassius Van Slyke. Since the studies were abruptly stopped in 1948 (see below), there were no further grants.

Study protocol

The rationale and clinical study plan clearly followed a defined logical pathway.

Determining the pathogenicity of well characterised strains

Since Treponema pallidum could not be cultured in vitro, the organism was maintained by serial passage in rabbits. The investigators were concerned about the pathogenicity of pedigree strains. For instance, the Nichols strain had been passed in rabbits since the early 1900s. There was some controversy over whether the serial passage resulted in decreased infectivity of the strain compared with the strains that were circulated in the communities. Therefore, initial work was focused on understanding the infectivity of these strains in experiments performed on human patients.

Developing a ‘natural’ model of transmission and infectivity using commercial sex workers

Could a ‘natural model’ of infectivity be developed? The initial ‘natural infection model’ would be transmission through sexual intercourse, focused on understanding the transmission efficiency from commercial sex workers (CSW) to potential clients. Subsequent experiments would involve providing postcoital prophylaxis after intercourse.

The clinical plan involved recruiting CSWs, intentionally infecting them with cervical application of syphilitic material obtained either from rabbit testicular homogenates or directly from human chancres, and then testing the clients at defined postcoital intervals. CSWs were recruited from a variety of venues in Guatemala. These CSWs included young girls down to the age of 16 years, experimentally infected with T pallidum, and subsequently also Neisseria gonorrhoeae, in other experiments. They were then instructed to have intercourse with either prison inmates or soldiers. Both groups were evaluated immediately in the postcoital period and serially thereafter.

Interestingly, the experimental finding was that the infection rate for both gonorrhoea and syphilis was low, commonly less than 10% and, therefore, was not useful for preventive experiments.

Developing direct inoculation models of human infection

After determining that the CSW ‘natural infection model’ was not effective, alternative approaches were pursued and developed. Cutler and his group moved on to other populations with a ‘direct infection model’. These experiments included developing infection models in humans, especially men, using a variety of inoculations and attempting to understand which is the most efficient way of inducing the infection in the human host. The subject population included individuals recruited from an insane asylum, prisoners and soldiers.

Studies included placing of pledgets under the foreskin, as well as subcutaneous injection, and even scarification on the penile mucosa, which then would result in ulcerations. The infected material used in these experiments was either rabbit testicular homogenates, or exudate/chancre materials obtained from infected patients. The notebooks describe different series of experiments where the infected material was placed at different inocula and different time intervals. The studies included careful photo documentation of all subjects, and the photography was performed by Dr Cutler's wife. After the inoculation was completed, the subjects were carefully followed and documented, in terms of their serological response, as well as whether or not they were treated. All lesions that developed were evaluated by dark-field microscopy. Serological evaluation included cerebrospinal fluid (CSF) examination of a majority of subjects, often serially. Infection rates were documented, and after infection was established, the subjects were treated, typically with long courses of intramuscular penicillin preparations.

Studies were performed to compare the virulence of street strains of T pallidum obtained from infected individuals with the well-pedigreed rabbit strain. Comparative inoculation studies were compared. The rabbit strain materials were testicular homogenates from infected rabbits. The human material was obtained from chancre exudates or homogenates collected from chancres obtained in patients in the venereal disease ward in a local hospital. Individuals who received inoculations and became infected then became potential donors. The studies demonstrated no difference in pathogenicity.

Ascertaining the preventive efficacy of prophylactic preparations

The prophylaxis studies were conducted in a similar manner. For instance, in order to study the effectiveness of prophylaxis, direct application to intact penile mucosa was performed using the Nichols rabbit strain, isolated from the testicles of rabbits 32 days after inoculation. Similar studies were done with material obtained directly from chancres of infected patients. The group was divided into a control group and a prophylaxis group. After brief cleansing with a cotton pledget, inoculation was performed, and those in the prophylaxis group were given orphus-mavarsun for prophylaxis. Orvus marpharsen prophylaxis was applied at designated times after exposure, and syphilis infection rates were calculated in the subsequent months. Similar postexposure studies were performed with penicillin where different doses of penicillin were administered 24–48 hours after the inoculation was performed

In order to determine how well the spirochete could penetrate intact mucous membranes of the gastrointestinal tract, patients were given 20 cc of distilled water with 1 cc of testicular material with 1.04×10⁷ organisms per cc and followed afterwards. The intent was to understand transmission through kissing or oral-genital contact.

After the penile inoculation, pledget and scarification infection models were established; each was then repeated with application of orvus-mapharsen prophylaxis at different time periods after exposure. Serial serology and CSF examinations were performed to evaluate the impact on infection rates.

Developing systemic infection and central nervous system infection models

A small number of patients were inoculated intravenously with rabbit emulsions to establish a model of secondary syphilis. A small number of subjects were inoculated intracisternally with infected material to establish a model of acute central nervous system syphilis (reference,2 p 56).

Number of subjects

The presidential commission performed a comprehensive review of all the clinical study documents, notecards and photographs, and compiled a spreadsheet of all the results from all the documented subjects and their results; and this spreadsheet is available online at (http://bioethics.gov/cms/node/650).

In total, there were 5540 individuals who were involved in the clinical experiments, of which 1,308 were documented to have been intentionally exposed to, or inoculated with, T pallidum, N gonorrhoeae, or Hemophilus ducreyi. The true actual number may be different because of poor record keeping, the potential that individuals may have been subjects more than once, and the similarity of many of the surnames in Guatemala. The subjects not clinically infected were largely involved in population-based serological and observational studies, which included large numbers of school children.

Of the 1308 experimental infection subjects, accurate documentation for treatment is available for 678. These subjects included highly vulnerable populations, including prisoners, patients at the mental health hospital and under-aged children. Treatment was defined as ‘any treatment’ which, therefore, may be an overestimate of effective treatment since many of the subjects were prison inmates, psychiatric hospital patients, CSWs and soldiers, in a resource-poor setting. Some of the reported regimens were quite intense (2 million units of penicillin intramuscularly every 2 h), and it is highly unlikely that in the primitive conditions of an asylum in Guatemala in the 1940s, that this would have been widely implemented. There were clearly no indications that appropriate management or follow-up was provided.

Issues that arise from the Guatemala studies

The Guatemala studies differ substantially from the contemporaneous Tuskegee experiments in that Tuskegee represented an omission of treatment in patients who were diagnosed with syphilis. By contrast, in Guatemala, subjects were intentionally infected by the study staff without their informed consent.

Historical context

The historical context for the Cutler studies suggest that within the context of what was known and standard at the time, there were ethical wrongs.

The same investigators in 1944, conducted experiments at the Terre Haute (Indiana) Prison on experimental gonococcal infection. Interestingly enough, during these studies, there was a clearly established principle of consent in that assent from the subjects was required for participation.11 Although certainly, these requirements do not meet current standards of research on prisoners or other individuals without full civil rights, there was clear recognition of autonomy, which is one of the principles of medical ethics.

The Nuremberg Trials of 1946 established the principles of informed consent as well as the importance of recognising the potential abuses of clinical research. An argument has been made that in contrast with the current situation, even in the concurrent times, these trials and their findings were not as well publicised, and had little mainstream impact on clinical research.12

There was a sense of war-time exigency. When the project was planned there was a large military imperative, and in the context of venereal diseases which had recently become medicalised. The medicalisation of venereal disease made this a military problem. Furthermore, there was an emerging culture of scientific inquiry in which the ideal situation was proposed that scientific research occurred in the best situation when there was minimal scientific oversight. There was also a cultural sense that the USA and Western powers, victors of World War II, were morally correct, and this type of research could not occur in the USA, and was actually reported in a New York Times article in 1947 as ‘ethically impossible’.13

Vulnerable population issues

These studies used multiple groups that would be classified as vulnerable populations under current practice. These include prisoners, persons with mental illness, persons with limited literacy and cognition, and CSWs. The correspondence between the investigators indicates that they were aware that there were sensitive issues in studying these populations. The content of the correspondence speaks for itself.

In 1947, Dr Robert Arnold wrote to Cutler describing the studies evaluating CSW transmission.

Cutler noted that many of the patients in the psychiatric hospital did not know their names and were designated by staff to participate. Patients were given cigarettes as inducements to participate, and the description clearly indicates that the subjects lacked judgment capacity and autonomy. In his experimental journal, Cutler reported:

The patients would attempt to make numerous trips past the physician, for bloodletting, cisternal puncture or examination, just to augment their supply of tobacco—Of the hundreds of cisternal punctures none resulted fatally, and patients minded the procedures so little that they would frequently line up day after day for a puncture just to get the two packs of cigarettes given to each individual examined.

The study was known in the scientific community of sexually transmitted disease (STD) researchers. Besides being approved by the study section in 1946, correspondence in the scientific community clearly indicates that the studies were of substantial interest.

Dr Thomas Turner was a well-known syphilis researcher and epidemiologist, was a member of the 1946 study section, and directed the US military venereal disease prevention efforts during World War II. He later became dean of the Johns Hopkins University School of Medicine from 1957 to 1965.

The investigators expressed concern about transparency or public knowledge of the research

In 1947, Cutler's diaries and research report narratives start expressing concern that persons outside the scientific community would find out about the project. They also became aware of Kaempfer's article in the New York Times13 referring to the ethics of human experimentation.

THE PUBLICATION RECORD AND CONSEQUENCES FOR THE SEXUALLY TRANSMITTED INFECTION COMMUNITY

The data from the 1946 to 1948 Guatemala studies work was never published. The lack of publication is one of the most intriguing aspects of this investigation, since Cutler and his collaborators actively published, including the important early penicillin studies and the Tuskegee studies. Therefore, the sparse publication record, in the face of such an enormous and prolonged field effort, is very unusual. A 1952 comprehensive review in Public Health Reports by Arnold and Cutler of penicillin in syphilis does not mention the Guatemala studies at all.14 In particular, it is difficult for me to imagine that based on the prophylaxis experiments that appeared successful, that the investigators would not have wanted to publish unless they were specifically directed not to, or were concerned that there may be adverse fallout from the publications.

Thomas Parran and the American STD association dilemma

At the time of these studies, Thomas Parran was the surgeon general of the USA. Dr Parran was a prominent public health advocate, as the architect of the US Syphilis Control Program, and was the author of the popular book, Shadow on the Land,16 which focused on destigmatising syphilis control in the 1930s and as we know it. He is acknowledged to be the father of syphilis control. However, Dr Parran did serve on the USPHS study section which approved the studies described in this paper, and although he never directly wrote about the Guatemala studies, he is referred to in a letter which has potentially damning implications.

In February 1947, during the same month when the researchers began sexual intercourse experiments in the Guatemalan army, Dr G Robert Coatney, a Public Health Service malariologist, wrote to Dr Cutler about surgeon general Parran's interest in his work.

This comment prompted a debate among the members of the American STD Association (ASTDA). The ASTDA lifetime achievement award is named after Dr. Parran and the Association debated whether the eponym should remain. The opposing arguments have been published in Sexually Transmitted Diseases.16–20 After a vote of the membership, the ASTDA voted to rename the award in April 2013 as the ASTDA Distinguished Career Award.

An assessment

Can individuals be held responsible for events that occurred more than 60 years ago at a time when there was societal acceptance of attitudes, behaviours and prejudices which are no longer acceptable? Are we fair to judge these individuals in the 1940s by contemporary ethical standards? We often encounter situations where historical and cultural norms, although repugnant now, were the societal standard of the time. Admittedly, this is a difficult issue, fraught with many dilemmas, especially when working with an often incomplete record that is devoid of any qualitative cues.

Nevertheless, even when considering historical and cultural relevance of clinical research in the immediate post-World War II era, there is consensus that there were substantial breaches of appropriate moral conduct even at the time.

For instance, the principle of consent for experimental clinical research infection had been established since the early twentieth century. In their review, the Presidential Commission concluded that the Terre Haute prison experiments in 1944 incorporated a consent procedure. The Nuremberg Trial findings, although not widely disseminated to practicing physicians, were certainly known to the scientific elite and the USPHS leadership. Finally, the investigators’ correspondence clearly indicates concern over the knowledge and transparency of the project and their procedures. I suggest that this belies their own concerns that their activities were not exactly ‘kosher’.

The fatal flaw of Cutler and the USPHS colleagues was their fervent unchecked belief in the scientific method, and the hubris that the experiments could be done free of ethical concerns. As clinical researchers, we should be humbled by what happened in Guatemala, and the 2011 report1 reads like a tragic novel, but unfortunately is true. Academic researchers have an inherent conflict of interest—where our ambition to succeed and publish has the potential to conflict with the human rights of our subjects. We owe our subjects the utmost in integrity and in being honest with ourselves about these conflicts.