Zenilman, Jonathan M. MD
In 2010, I was asked to be a technical consultant to the US Presidential Commission on Bioethical Issues, which was investigating the experimental studies of sexually transmitted infections performed by the US Public Health Service in Guatemala in 1946 to 1948 and led by Dr John Cutler. This investigation was precipitated by the serendipitous discovery by Dr Susan Reverby of Dr Cutler’s papers at the University of Pittsburgh.1 These files contained the Guatemala study protocols, laboratory books, correspondence, patient records, and patient photographs. Reverby is a historian at Wellesley College, who was researching Dr Cutler’s role in the Tuskegee studies of untreated syphilis.2–8
In 2010 to 2011, the Commission performed an intensive investigation that included review of all the Cutler source materials, as well as materials obtained from an extensive search of federal and private archives, and site visits to Guatemala. Public hearings were also conducted, and the full report Ethically Impossible was published in September 2011.9 A description of the timeline and content of these experiments has been published in both Sexually Transmitted Diseases10 and Sexually Transmitted Infections,11 and therefore, these will be described here only in the broadest terms. In addition to the published record, the original source documentation from the Cutler archives, including the patient records (with personal identifiers redacted), correspondence, and experimental notebooks, has been posted online by the US National Archives.12
In the course of the Commission’s work and in my own evaluation of the documents, I became convinced that the Surgeon General at the time, Dr Thomas Parran, was aware of the Cutler experiments. Dr Parran is universally recognized as the founder of the modern sexually transmitted disease (STD) control program in the United States and a progressive force in health policy during his tenure as Surgeon General between 1934 and 1948. He was a recognized outspoken public figure of the time and was often cited in the popular press, including being on the cover of Time magazine on October 26, 1936. In recognition of Dr Parran’s contributions, since 1972, the American STD Association (ASTDA) has named its highest career achievement award as the Parran Award and is presented annually to an individual with “for long and distinguished contributions in the field of STD research and prevention.”
In 2011, the ASTDA held a public discussion and review of the Parran award and, in light of the Guatemala revelations, of whether the award should be de-eponynomized. A major part of the debate included discussions on how to recognize Dr Parran’s titanic contributions to the STD prevention, control, and policy. This process included public presentations of the issues at the 2012 National STD Prevention Conference in Minneapolis by members of the Presidential Commission, publication of background documents and position papers advocating for both pro and con positions related to de-eponymomization,13–16 and spirited discussions on the ASTDA public Web site (www.astda.org). In early 2013, the ASTDA membership voted and decided to change the name to the Distinguished Career Award.
After my brief discussion of the Guatemala studies, I will review the extraordinary life of Dr Thomas Parran and then pose a number of lessons that we can learn from this experience. The story is nuanced, and my conclusion is that this presents to us a cautionary tale of clinical research and medical hubris, which is highly relevant to us in contemporary clinical research and public health practice.
THE GUATEMALA EXPERIMENTS
The genesis of the 1946 to 1948 Guatemala studies was driven by public health and military exigencies. By the end of World War II, the efficacy of penicillin therapy for the treatment of syphilis and gonorrhea had been elucidated in clinical studies and had been documented in the medical literature.17–20 These developments were revolutionary because they resulted in highly effective, short-term therapy with minimal toxicity. The original clinical studies were conducted by the USPHS Venereal Disease Research Laboratory in 1943 to 1945, which at that time was located at the US Public Health Service Hospital in Staten Island, New York. These studies had tremendous implications for the military. Venereal diseases were a major cause of medical disability in the armed services and, hence, were the focus of both primary and secondary prevention campaigns, which included abstinence promotion and condom provision.21 Nevertheless, sexually transmitted infections were highly incident in the military operational areas. The long-term treatments required caused concern over military deployability.22
There was tremendous interest in the Public Health Service and in the military medical commands for developing appropriate treatment protocols for individuals exposed either to a person with known sexually transmitted infection or to an individual who had suspected exposure. The contemporaneous standard texts, including the renowned Stokes text,23 did not address this issue. Therefore, the underlying key question to understand the efficacy of postexposure preventive treatment was as follows: Can a preventive regimen be evaluated in a model where humans are infected under controlled conditions? The eventual goal was to develop a series of 3-arm studies, where individuals would be experimentally infected with STD pathogens (Treponema pallidum, Neisseria gonorrhoeae, Haemophilus ducreyi) and then receive either no treatment (control group) or treatment with either systemic penicillin or an arsenical ointment (Orvus-Mapharsen). Efficacy would be measured over time by comparing the experimental and control groups for the development of symptomatic and/or serological evidence of infection.
Guatemala was chosen as the experimental venue because of a personal relationship between Dr Cutler and other PHS officials with Dr Juan Funes, a Guatemalan physician associated with the Ministry of Health, and other Ministry officials. Dr Funes had trained at the Venereal Disease Research Laboratory, was well known, and was ambitious. Furthermore, there was a small US Army contingent resident in Guatemala, and therefore, the investigative team had access to regularly scheduled transport flights. The study was funded by the US National Research Council, a forerunner of the current National Institutes of Health, and was reviewed by the Syphilis Study Section.
To implement the experiments, a large number of preparatory work was required and was performed. These studies, performed in human subjects, were described in detail previously,9–11 included the following:
1. Demonstration that the classic treponemal strains in rabbits were pathogenic and infectious in humans.
2. Developing a human infection model for syphilis and gonorrhea in commercial sex workers and then exposing clients to the infected sex workers under experimental conditions.
3. Developing human infection models for syphilis and gonorrhea, which included direct inoculation of infected material. Inoculation methods included direct application, subcutaneous injection, scarification, and intraurethral inoculation. Follow-up studies included periodic serology and clinical observation, extensive photodocumentation, and subsequent treatment. Materials used for transmitting infection included for syphilis, either rabbit testicular homogenate or transfer of human material. For gonorrhea, the infectious materials were either culture material or infected human exudates.
4. After characterization of the human infection models, the postexposure treatment studies were performed.
5. In a subset of syphilis studies, direct intravenous inoculation or intracisternal (cerebrospinal fluid) inoculations were performed.
The research began in 1946. The populations studied for the transmission and prophylaxis experiments included patients at a psychiatric hospital, prisoners, commercial sex workers and, in some instances, soldiers. Informed consent, even by the standards of the time, was not obtained. Although participants who developed infections were treated, there were clearly large numbers of participants where the documentation of treatment was either incomplete or nonexistent. All of the studies performed were ethically flawed. In sum, 1308 patients were involved in intentional exposure experiments, 678 received treatment, and, for the remainder, treatment was undocumented.
Ironically, although these studies were in full force, the New York Times science correspondent Wolfgang Kaempffert published a small article on April 27, 1947, commenting on recent experimental findings on postexposure treatment experiments conducted in rabbits.24 “...Doctors Harry Eagle, Harold Magnusson, and Ralph Fleischman of the United States Public Health Service, the Johns Hopkins School of Hygiene and the University of North Carolina had discovered that small doses of penicillin, injected within a few days after exposure prevents syphilis from developing. The case holds good for rabbits, but no tests on human beings have yet been made. To settle the human issue, quickly it would be necessary to shoot living syphilis germs into human bodies just as Doctor Eagle shot them into rabbits. Since this is ethically impossible, it may take years to gather the information needed” (italics added).
In 1948, the Guatemala experimental efforts abruptly halted. Despite an intensive investigation and search of the Government archives, there is no documentation of how this decision was made or who gave the order to stop the experiments. Cutler and his colleagues in Guatemala never published anything on the Guatemala efforts despite the enormous efforts that they invested in the research. The only publications were from serosurveys conducted in children and included Drs Funes and Cutler as coauthors.25,26 Many of the same USPHS investigators, including Cutler, were involved in the infamous Tuskegee studies and published extensively on that work into the 1970s3,4 and clearly did not shy from controversy. Furthermore, the finding of the records in Cutler’s personal archive at the University of Pittsburgh, rather than in the records of the Public Health Service, raises questions about their provenance and Cutler’s motivations for storing them in this manner.
A Discussion of the Historial Context and Contemporaneous Ethics
The historical context of the Cutler work has to be understood within the evolving doctrines of informed consent in medical research. The Commission considered as precedent the Terre Haute, Indiana Federal Prison experiments, discussed on pages 13–23 of the Commission report.9 These were gonococcal inoculation experiments conducted in 1944 in the US Federal prison in Terre Haute Indiana in prisoner volunteers. Although there was no formal written informed consent procedure, there was a principle that the participants needed to be informed and to participate voluntarily. Despite the paternalistic nature of much medical practice and research, the doctrine of agency and consent had been developing since the late 19th century in Germany.
Modern clinical research ethics developed after World War II as an outgrowth of the 1946 Nuremberg trials of Nazi physicians. The initial codification, the Nuremberg code, which continues to be a key source document for medical ethics,27 highlights the importance of individual agency, ethical principles of justice, equipoise and beneficience, informed consent, and the primacy of research participant safety. Besides the governmental agencies, these principles were adopted by the major medical societies, including the American Medical Association, which published in JAMA in 1947 “...Consent of the subject must be obtained. All subject s must have been volunteers in the absence of coercion in any form....”28
However, in the immediate postwar period, there were major counterforces to participant-centered research and human rights.
During wartime especially, national security exigencies may preempt other rights or initiatives. Deployability of soldiers was perceived as a major national security concern. There are other well-known examples of experiments without consent that occurred with both radiation and infectious agents.29
At the time, with the rapid advances in medical practice and in research, there was an emerging culture of scientific inquiry in which the ideal construct was scientific research with minimal government oversight. In large part, this was driven by the medial hubris the time, in which the physicians and medical researchers claim that they had participant/patient’s best interest at heart.16
The United States and allies, having recently triumphed over Nazi Germany and Japan, clearly determined itself to be in an ethically superior position. Current terminology still refers to the conflict as a “Good War.” As Kaempffert’s quote clearly indicates, that unethical clinical research was something that was not part of the US culture.
The Role and Responsbility of Dr Thomas Parran
Dr Parran, as Surgeon General, clearly was aware of the Tuskegee study and also had oversight of the National Research Council, which funded the Guatemalan studies in 1946. Although Dr Parran was never directly implicated in the Guatemala studies, there are suggestions in the correspondence that he was aware. I would further expect that his awareness would be heightened because these studies were in his particular area of intense interest for the preceding 25 years. In the Guatemala/Cutler correspondence files, there is an indirect reference to Dr Parran.
On February 17, 1947, the same month that the researchers in Guatemala began sexual intercourse experiments in the Guatemalan Army, G. Robert Coatney, a PHS Malariologist, wrote Dr Cutler about Surgeon General Parran’s interest in his work:
I saw Dr Parran on Friday (February 14), and he wanted to know if I had a chance to visit your project. Since the answer was yes, he asked me to tell him about it and I did so to the best of my ability. He was familiar with all the arrangements and wanted to be brought up to date on what progress had been made. As you well know, he 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….30
Dr THOMAS PARRAN—BACKGROUND AND ROLE AS A SOCIAL REFORMER AND PROGRESSIVE PUBLIC HEALTH FORCE?
Dr Parran (Fig. 1) was born in 1892 to a Southern Maryland family that included prominent state legislators and congressmen. He received his medical degree in 1915 from Georgetown University and became a US Public Health Officer in 1917, and during the 1920s, he became interested in the societal impact of syphilis and other venereal diseases.31
Parran recognized that there were tensions in developing programs to control STDs. The Social Hygiene movement, which arose during the 1920s, focused primarily on prevention and harm reduction approach and advocated for public health services and funding. Other movements, which were either grounded in moralistic traditional approaches or even in Freudian approaches, tended to look at STDs as a more judgmental type of issue. These tensions, in one form or another, continue through contemporary times. Societal changes changed the dynamics of STD in the 1920s. especially the automobile, which provided mobility and opportunities to meet new partners and the liberalization of the 1920s, which was expressed in a variety of ways in the social culture.32
During the 1920s, the public health community began to recognize that these infections had tremendous impact on public health and also economic productivity. Dr Parran chaired a committee to address the syphilis problem, which was cosponsored by the Dupont Corporation, the Rosenwald fund (the philanthropic arm of Sears, Roebuck), and others. The committee called for increased medical services, diagnostic testing, and research into syphilis. There was recognition that medical care was not standardized, and the evidence for many of the contemporary therapeutic approaches was sparse. This recognition eventually resulted in Dr Parran’s organization and implementation of the Cooperative Clinical Group, which was a multicenter clinical trials consortium established to develop clinical trials for syphilis and which included prominent academic institutions such as Johns Hopkins and Vanderbilt.
In 1930, he was appointed by Franklin Roosevelt, who was at that time the governor of New York State, as State Health Commissioner, which was followed in 1936 by his appointment by then President Roosevelt as US Surgeon General.
Parran’s cardinal moment occurred on November 19, 1934, when he scheduled a radio address on the Columbia Broadcasting Network (now CBS) to discuss publicly the syphilis issue to a mass audience. The prepared text was as follows:
We have made no progress against syphilis though its end results crowd our jails, poor houses and insane asylums. Yet there are specific methods of controlling syphilis. We need only to do what we know how to do in order to wipe out syphilis as a public health problem.
This was for the time, scandalous, and CBS refused to broadcast the address because it contained syphilis in the text. The following day, Dr Parran shot back at the network and was quoted in the New York Times:
That a hopeful view of relief from their dangerous malady might be more welcomed to the half million persons in the United States who acquire this disease each year than the veiled obscenity permitted by Columbia in the vaudeville acts of certain of their commercial programs.33
This, in fact, is manifest demonstration of Parran’s ability to engage the public and his commitment to these ideas and not to avoid public controversy.
Concurrently, Dr Parran was writing his book Shadow on the Land,34 whose audience was the general public and was an educational primer on the natural history, transmission, and control of syphilis. Shadow on the Land, as suggested by the title, advocated openness and destigmatization and a generally progressive view of STDs control. These views included education campaigns, providing health care in a nonjudgemental setting, community-based approach, focus on counseling and testing, and development of adequate public health and clinical infrastructure (Figs. 2 and 3). He was critical of the lack of adequately trained physicians and health facilities. Besides the medical diagnostic and treatment issue, he also recognized and promoted the idea that these diseases were rooted in the community and that infection can be spread through networks. The network hypothesis is clearly presented in Shadow on the Land but is also dramatically presented in a USPHS film from 1942.35
He considered Scandinavia as the model example of how to manage these diseases, and his preparatory work for the book included a visit:
Syphilis in Denmark is considered a disease. It is discussed and publicized as such. Nobody minds talking about it... The Danes are a bit amused at our inhibitions.
Parran was also prescient in identifying that STDs are not an individualistic issue, but rather a societal concern:
The treatment of the disease is no longer the concern solely of the individual; the community as a whole has a financial stake in the untreated illness.
Ironically Parran’s book received an enthusiastic review by the by the same New York Times science correspondent, Wolfgang Kampffert36:
Dr Parran’s Shadow on the Land is a vigorous survey of “The most urgent public health problem in this country today!
Besides the public, he also reached out to the medical and scientific communities, with articles in professional journals and speeches.37 Parran’s Shadow on the Land was the blueprint for the US syphilis control policy for the subsequent 75 years. The program he proposed (Fig. 3) was also a forerunner of the widely implemented HIV counseling and testing algorithms and screening programs developed in the mid to late 1980s.38,39
Parran became a well-known figure in the popular press and clearly had impact and was able to promote advocacy for disease control and leverage his influence locally. For example, the Baltimore Sun reported:
...Public interest in Parran’s speeches was so great that when city budget officials refused a health department request for an extra $21,000 to combat syphilis, their action was publicly denounced as ‘incredible.’40
As the storm clouds of World War II developed, under Parran’s leadership, the US Health Service performed a series of studies demonstrating that syphilis prevalence was extremely high in the United States, especially in the South.41 Serological evidence of syphilis prevalence was 10% to 17% of draftees being selected for service. Furthermore, contracting a venereal disease while in the military was considered a breach of discipline and punishable under the military justice system. In 1940, this was changed and venereal diseases were treated as medical conditions.21,32 This change occurred under the leadership of Dr Thomas Turner, a Johns Hopkins medical school faculty member, who directed venereal diseases control services for the US armed forces in World War II. Turner was a treponemal and syphilis expert, a core member of the Cooperative Clinical Group, and incidentally was Dr Parran’s cousin (personal conversation of the author with Dr Thomas Turner, 2000).
Parran used war time preparedness analogy in describing the domestic syphilis and venereal diseases control program34:
The whole public health program...may be stated very simply. It consists of alertness along the entire front of preventive medicine to be sure that ground gained is held and consolidated, and a concentrated attack upon those sectors where the greatest saving of human life can be made....
Parran was a proponent of social justice. He identified through many of his writings health in the south and in African Americans in particular as major health problems. Under his leadership, USPHS provided medical sanitization companies, which targeted black populations in the Deep South and focused on improving nutrition, sanitation, and access to medical care. He promoted training of black nurses and physicians and supported a stronger system of hospitals and clinics especially in underserved areas. In his syphilis prevention efforts,42 when he encountered health care disparities and segregated facilities at the Johns Hopkins Hospital in Baltimore, he responded by providing resources and professional expertise at the Baltimore City Health Department.
However, on a national level, and especially in the South, his efforts and resources were limited by what is now termed the Deluxe Jim Crow Compromise.42 To pass the progressive New Deal legislation in the face of near unanimous, Republican opposition President Roosevelt needed the congressional support of the Southern Democratic caucus. At that time, the Democratic party consisted of a Northern liberal wing, which prioritized labor social issues, and a Southern conservative wing, which was entrenched in maintaining the racial status quo. Roosevelt needed the Southern Democrats to pass the New Deal. The Deluxe Jim Crow compromise was a deal where in return for the Southern Democrat votes, services and programs to African American communities in the Deep South would be deliberately underresourced, and there would not be attempts to promote racial equality.
During the war, Parran was also concerned about the public health impact of defense-related issues on the home front. He was especially concerned about reports of biological weapons development by the Germans and initiated programs for biodefense.43 He oversaw the development of the Centers for Disease Control and Prevention in 1946. For wounded soldiers returning from the World War II conflict, he advocated for research in rehabilitation and increasing the availability of rehabilitation services.44
Throughout his career, he was a staunch supporter of universal health care access and national health insurance.10,45,46 His 1968 obituary in the New York Times emphasized that
...In his time, Dr. Parran was a bogeyman to organized medicine because he argued that all people had a right to good health irrespective of their means. He said repeatedly that the Government should provide expert medical care for those who could not pay a private physician’s fees....31
As a result of Parran’s staunch advocacy of universal health insurance and support of President Truman’s proposal in 1946, he was censured by the American Medical Association, which at that time was aggressively opposed to national health insurance and mounted media campaigns against “socialized medicine.”47 Parran also criticized pharmaceutical companies for inaccurate advertising and criticizing them for making “extravagant” claims. Dr Parran left the post as Surgeon General in 1948 over a political dispute with higher administration officials.
As Surgeon General, he was a progressive force. He developed the national program for syphilis and overall venereal disease control. He professionalized the Public Health Service and made it a home for ambitious physicians interested in national service. He developed clinical research within the PHS and recognized the importance of developing a national, taxpayer-funded medical research infrastructure and developed the National Institutes of Health as the lead federal agency supporting medical research. He was a proponent of the social and economic determinants of health and believed that universal health care access was critical to mitigating disparities and improving economic productivity. He was a proponent of improving nutrition as a population health issue on both domestically and internationally. He was a proponent of health care worker training, for nurses, physicians, and paramedical health workers, especially for African Americans in the Southern United States. He developed and implemented major programs in maternal child health and tuberculosis control. A consistent theme in Dr Parran’s writings is a sense of justice and “Doing the right thing.”
WHAT WAS Dr PARRAN’S FLAW? OR DID HE HAVE ONE?
The fascinating dilemma of Dr Parran is that this progressive social reformer and public health advocate also oversaw the Tuskegee and Guatemala studies. How do we reconcile this? Did he have a fatal flaw or moral blind spot? I propose that he was more a product of his times and in this way is a tragic figure.
The principles of biomedical ethics, which were developed in Nuremberg in 1946 and codified by the Belmont Report in 1972 ironically after the disclosure of the Tuskegee Study, emphasize the 4 major components: autonomy, beneficence, nonmaleficence, and justice.
These concepts have been extensively described27,48 and should be seen as a frame work to evaluate studies, concepts, and individuals.
The historical context of the Guatemala studies and their relationship to contemporaneous medical ethics have been a key feature of the Parran renaming debate. Are there absolute, that is, timeless ethical precepts, or should investigators be judged in a contextual framework? Most ethicists consider that both should be considered. For example, Nazi physicians within their own constrained world were operating what they considered to be a moral framework; however, the framework itself was morally flawed and violates basic universal ethical principles. The second concept is the theory of moral progress, in which societal and perhaps even overall behaviors were considered to be moral at the time, but later, these were clearly seen to be invalid, unethical behaviors. For example, the informed consent process in 2013 is much different than the process in 1940, even if participant assent/consent was obtained. In Guatemala, there were absolute ethical issues—there was no informed consent, there was evidence of participant deception, there was substantial real harm to the participants, and the participants were highly vulnerable populations.
How should we assess Dr Thomas Parran? I believe that Thomas Parran was a humanist, had a societal approach to health, and clearly had political moxie and courage. However, the Tuskegee and Guatemala studies clearly speak for themselves. I think we should conclude perhaps that all of us who do clinical research are susceptible to moral failing, and we therefore need to be vigilant. Contemporary historians do not believe that Parran had a fatal flaw per se16 and consider that he was subject to the paternalism of scientific inquiry at the time as well as overall societal attitudes toward race, as well as the current of moral superiority in the United States in the immediate post–war period.
The Parran story is one of a cautionary tales of a perfect storm of scientific hubris, the pressures of national/military exigency, paternalistic attitudes (which were existing at the time), and personal ambition.
I believe that there are important lessons from this experience:
* We need to be very careful of clinical research bypassing ethical safeguards, especially that justified by national security or military exigency. We have seen contemporary examples with the post-9/11/2001 experience and proposals to suspend human rights and liberties because of national security.
* We need to recognize that there is always a slippery slope in clinical research and ethics. This slippery slope exists, in large part, because there is an inherent conflict of interest. The conflict of interest is driven by ambition, responsibility to sponsors, and timelines, budgetary considerations. Therefore, as clinical researchers, we need to be highly conscientious and cognizant of these issues, and develop and implement structural protections to protect our participants and also to protect ourselves.
* Finally, we need to recognize the continual issue of vulnerable populations and our responsibility to them as health care providers, physicians, and clinical researchers.
One of the arguments made by the contemporary historians in our analysis of Parran’s life and the Guatemala studies is that if Parran was assessing this question, he likely would have recommended changing the award. In a graduation address given at Skidmore College in 1938, Dr Parran referred to the National Archives building in Washington46
...carved on the pedestal to the left the simple factual statement, ‘What is past is prologue.’ To the right is the simple admonition ‘Study the past.’ My profession is medicine: my specialty public health. My task as a government official in a technical service is first that of foster research, which adds to our store of scientific knowledge; and second of making practical application of scientific knowledge to today’s problems.
The first statement carved at the Archives entrance voice my philosophy and the philosophy of this whole generation of the men of science; what is past is prologue. The second statement represents the first and most and most important of our methods ‘Study the past.’ There remains a final step: Act boldly upon the principles shown valid by the past.46
As clinical researchers. we need to be watchful for potential conflicts of interest. In our area of sexually transmitted infections, one of the points made at this conference by Dr Ken Mayer was that our patients are not “risks” or “vectors,” and we need to caution about depersonalization. Dr Thomas Parran did great things and was a social reformer, but Tuskegee and Guatemala occurred on his watch. Therefore, we are challenged in how to honor his legacy and accomplishments but recognize his failure as one that which could occur to any of us.
Finally, my vote on the question was nuanced. I feel that Parran was clearly a product of his time, although in many ways was ahead of his time. I felt regret at de-eponymomizing the award because of the tremendous contributions to our field and to public health in general and to public health policy. However, my vote was influenced also by the unique circumstances of our profession.
Persons with sexually transmitted infections are often on society’s margins. As health care providers for the poor, disenfranchised, and marginalized and being quite proud of our providing care to these individuals in a nonjudgmental fashion, and as advocates for human rights, social justice, and health care, I believe that we as a profession and the ASTDA as an organization need to have an extraordinarily high ethical bar. Our commitment to this mission needs to be beyond reproach, and therefore, we need to be careful of even the appearance of any support for unethical research. I therefore voted for changing the name of the award. However, concurrently, we also need to recognize and even revere Parran’s enormous accomplishments in promoting public health and use his story as a source for continual self-reflection on our own clinical research activities.