Inoculation Syphilis Experiments in Guatemala:

Why did the U.S.

Government
Apologize?
Why was syphilis so important?
Crude Mortality Rates for Syphilis and AIDS
1900-1996

Douglas, J. M. JAMA 2009;301:769-771.

Why the focus on syphilis?
Although syphilis is currently considered to be an STD that can
be easily cured with penicillin, it is important to remember
that at one time, syphilis was a critical public health concern,
a very dangerous disease, and was assumed to affect
“races” differently.

Only in the 1930s was it even possible to speak about it in

public.

One of these concerns was to understand the “natural history” of

the disease and to determine if there was too much
“overtreatment” with the heavy metals of the pre-penicillin
era.

Even after penicillin proved to cure it in 1943, much was still

unknown in the 1940s about how the penicillin worked, what
it could do, and what the future might be with this disease.

While penicillin was proving a cure, another research question

was could it act as a prophylaxis before infection but after
exposure.?
Among the many other studies going on is one in
and around Tuskegee, Alabama

  1932: The U.S. Public Health Service begins a Study of

Untreated Syphilis in the Negro Male, in and around Tuskegee,
Alabama.

  African American men are the unknowing subjects and controls.

  The study will continue for forty years till 1972 when media outcry
forces its closing.

  Coding the medical records shows:

  The Tuskegee study tracked 427 men with syphilis.
  There were 185 controls.
  12 controls switched to the syphilitic arm of the study.
  There were a total of 624 subjects.

  The government does not infect the men in this study.

  All the men are assumed to be non-contagious (not all are) and in
the late latent stage of the disease.
Key Elements in the Study:

 Deception: men are told they are being

treated and that the aspirin, tonics and
diagnostic spinal taps are treatments
 No consenting except for the autopsy
 Promise of burial insurance and services
of a “private” public health nurse
 Goes on even after penicillin
 Continues even after ethics questions are
raised in the 1950s and 60s
 Finally ends in 1972/73 with media outcry
Rivers hands out drugs
Spinal Tap
Apology, Families/Men
Concern with
Prophylaxis
Prophylaxis
The Public Health Service had done experiments on prophylaxis in
gonorrhea at the Terre Haute Federal Penitentiary in the United
States in 1943.

In this prison, the volunteers were deliberately injected with

gonorrhea, but the PHS had found it difficult to get the men to
exhibit infection and the study was abandoned.
The Guatemalan Study Begins in 1946
 Grant RG65
  Given by The National Institute of Health, under the U.S. Public
Health Service (PHS)

  Given to the Pan American Sanitary Bureau (later PAHO) under

the direction of the Venereal Disease Research Laboratory of
the U.S. PHS.
  With the cooperation of the Ministry of Health of Guatemala,
the National Army of the Revolution of Guatemala, the
National Mental Health Hospital of Guatemala, and the
Ministry of Justice of Guatemala

Director is Dr. John C. Cutler, Senior Surgeon, U.S. PHS

Guatemalan contact is Dr. Juan M. Funes, Chief of Venereal

Disease for the Guatemalan Ministry of Health, who has also
trained with the PHS in the United States.
John Cutler s Legacy

 Public Health

 Family Planning

 STD/HIV

 Sexual Health
John C. Cutler
  Dates: 1915-2003
  Medical school: Western Reserve University Medical
School, 1941
  Joins PHS in 1942 as a commissioned officer and
remains in PHS till 1967, rising to rank of assistant
surgeon general
  Works at the PHS VDRL lab then in Guatemala
  Goes to India for WHO for VD demonstration project in
1949
  Organizes polio vaccination program for Allegheny
County Health Department in 1960
  Assistant and Deputy Director PAHO 1961-67
John C. Cutler

  Becomes Professor of International Health and heads

Population Division in the Graduate School of Public Health
at Pitt in 1967
  Works to make it possible for third world ob/gyns to come to
the US to receive training in reproductive health technology
  Chair of Department of Health Administration and Acting
Dean of the PH School 1968-69
  Involved in Tuskegee Study in 1960s and defends it on Nova
“Deadly Deception” documentary in 1993
  Remembered as a “much beloved professor”
  Pioneers research in the third world, devoted to providing
access to reproductive health services
  Publishes over 50 articles on his research
  Source: Jan Ackerman, “ Obituary, John C. Cutler,” Pittsburgh Post-Gazette,
February 23, 2003, http://www.post-gazette.com
35
 What Was the Purpose?

These studies were designed to obtain information about

methods of prophylaxis against syphilis; to increase understanding
of the effects of penicillin in treatment of syphilis; to assist in a
better understanding of the question of false positive serologic
tests for syphilis; and to enhance knowledge of the biology and
immunology of syphilis in man.
— John C. Cutler

Source: John C. Cutler, Experimental Studies on Human Inoculation with Syphilis, Gonorrhea and
Chancroid, Unpublished report, 1955, Cutler Papers, University of Pittsburgh Archives Service
Center
 Why Guatemala?
  Difficulty of finding population with infection that is contained for
study in the United States

  Long history of connection between the PHS and Latin America

through the Pan American Sanitary Bureau (now the Pan American
Health Organization)

  Connection with Juan Funes who trained at the PHS Venereal

Disease Research Laboratory

  Need the prostitutes as a way to deliver infection

  Prostitution was then legal in Guatemala and men in the

central penitentiary in Guatemala City were allowed visits
from prostitutes.
Infected prostitutes paid to visit
prison inmates

This group, lowest in the social scale of local prostitutes and

most frequently infected with syphilis and gonorrhea were to
be permitted, after discovery of presence of acute gonorrhea
or infectious syphilis, to continue going to the prison and
were to be paid by us for offering their service to any inmate
who desired to utilize her at no cost to himself.

— John C. Cutler

Source: John C. Cutler, Experimental Studies on Human Inoculation with Syphilis,

Gonorrhea and Chancroid, Unpublished report, 1955, Cutler Papers, University of
Pittsburgh Archives Service Center.
 How Many Were Involved?
  “In the series of syphilis studies, a total of 696 subjects or
individual experiments…were exposed to infection (by sexual
contact or inoculation). Of these 427 (61%) were judged to be
infected, of whom 369 (86%) received what was considered to be
‘adequate treatment’ with injections of penicillin (defined by the
investigators as > 3.4 million units.”

  “In the series of gonorrhea studies, a total of 772 subjects of

individual experiments…were exposed to infection (by sexual
contact or inoculation). Of these a summary report and
experimental logs indicate that 234 (30%) were infected, 233
(99.5%) of whom were stated to have received treatment with
injections of penicillin (300,000 units.)”
 How Many Were Involved?
 In the “chancroid studies…a total of 142 subjects were exposed to
infection by inoculation. Of these, a summary report and
experimental logs indicate that 128 (97%) were infected, 129 (93%)
of whom were stated to have received treatment with sulfathiazole (1
gram PO per day for 5 days).”

Source: John Douglas, “Findings from a CDC Report on the

1946-1948 U.S. Public Health Service Sexually Transmitted Disease
(STD) Inoculation Study,” (http://www.hhs.gov/1946inoculationstudy/
findings/html)
1946 Prison Research

The fear of what they saw was much more important to them than
the potential damage which mighty be done by syphilis years later
and could not be countered by promises of actual administration of
penicillin for syphilis and iron tablets to replace blood. In their minds
there was no connection between the loss of a large tube of blood
and possible benefits of a small pill.

—John C. Cutler

Source: John C. Cutler, Experimental Studies on Human

Inoculation with Syphilis, Gonorrhea and Chancroid, Unpublished
report, 1955, Cutler Papers, University of Pittsburgh Archives
Service Center.
1947 Blood testing
at National Orphanage
With the cooperation of the Guatemalan government, the
researchers turned to 438 children between the ages of six and
sixteen in the National Orphanage to study the blood tests, not to
give the children syphilis.

Three children who appeared to have signs of congenital syphilis

after repeat testing and examination were given penicillin.

Yet another eighty-nine gave positive results on their tests but

showed no clinical signs of the disease.

Finding that the problem was not with the antigens used in the
tests, the research physicians argued for the use of specific kinds
of blood tests with this kind of population to rule out confounding
factors they could not identify.
1947-48 Study of inmates
at national mental health hospital
and at army barracks.
Infected prostitutes cannot be used and women are not allowed to be
examined by men, even male doctors.

Decision is made to make an inoculum and to infect subjects, then offer

penicillin if they become infected.

The inoculum is difficult to make. They need to get bacteria from

syphilitic chancres, or from ground up testes of rabbits who also have
the disease. T. pallidum, the spirochete that causes syphilis, cannot be
grown in a culture. It cannot be transferred from the blood of one
infected person to another.
 Mental Health Hospital
PHS offers Dilantin (for epileptics who are a large part of the
population in the hospital.)

They also bought a refrigerator for biologicals, a motion picture

projector that supplied the sole recreation for the inmates, metal
cups, plates and forks to supplement the completely inadequate
supply available. Individual subjects were offered cigarettes: an
entire packet for inoculation, blood draws, or spinal taps and a
single cigarette for clinical observation.

Ibid., 25.
 Example
Example of Medical Record
of medical
record
Inoculation is done through the abrading of arms, faces, mouths
and men s penises. Other efforts use ingestion of distilled water
with the syphilitic mixture, spinal taps, and venipuncture of vein in
the forearm.

Transfer of the infection proves difficult.

Interest in prophylaxis is waning in the United States as penicillin

is being used more widely and proven its success in curing the
disease.
Deception and Ethics
 Officials in the hospital are not being told that the inoculum contains
the bacteria that causes syphilis.

 Correspondence between PHS officials demonstrates that they

know they are hiding something and that this could not be done in the
United States.

Malaria specialist G. Robert Coatney, who had done

prison malaria studies, visited the project in February 1947. In reporting to
Cutler after he returned to the States, he explained that he had brought
Surgeon General Thomas Parran up to date and that with a merry twinkle
[that] came into his eye . . . [he] said You know, we couldn t do such an
experiment in this country.
G. Robert Coatney to Cutler, 17 February 1947, Box 1,
Folder 17, Cutler Papers.

 Concern raised about the morality of doing this in the mental

hospital and about consent.
 Letter from R. C. Arnold
to John Cutler
I am a bit, in fact more than a bit, leery of the experiment with the
insane people. They can not give consent, do not know what is
going on, and if some goody organization got wind of the work, they
would raise a lot of smoke. I think the soldiers would be best or the
prisoners for they can give consent. Maybe I m too
conservative. . . . Also, how many knew what was going on. I realize
that a pt [patient] or a dozen could be infected, develop the disease
and be cured before anything could be suspected. . . . In the report,
I see no reason to say where the work was done and the type of
volunteer.
 Closing the Study
1948
Cutler is told to close down study, leave supplies for the
Guatemalans and return for another assignment.
 Comparisons
In Guatemala 1946-48 In Tuskegee, 1932-72

In Guatemala, the subjects (men In Alabama, the men already had

and women) are given syphilis. the disease and were supposed to
be in late latency.

In Guatemala, the subjects were In Alabama, the men were kept

given penicillin (even if not from treatment (even if not always
everyone is cured). successfully).
How Did the Study Come to
 1990 Light?
Cutler gives papers to the University of Pittsburgh archives

 2000s
Susan M. Reverby, doing research for her book on the study in Tuskegee,
finds the reports in Cutler s papers

 June 2009
Reverby returns to Pittsburgh archives to re-examine the papers and take
more notes

 May 2010
Reverby gives paper on the Guatemala research at the Annual meeting of
the American Association of the History of Medicine

  June 2010
Reverby writes the paper as an article for a special issue of the
Journal of Policy History on Human Subjects.
 July 2010
  Reverby sends a copy of the paper pre-publication to Dr. David
Sencer, former director of the CDC, who then asks if he can
circulate it to CDC officials.

  CDC officials call Reverby and send Dr. John Douglas to Pittsburgh
to examine the Cutler papers.

  Douglas report confirms Reverby s findings and analyzes the

numbers given the diseases and treated.

  CDC officials send the information up the chain of command to NIH,

DHHS, and then on to the State Department and the White House.
Top Left: Harold Jaffe
Top Right: Ezekial J. Emanuel
Bottom Left: John Douglas
What were the ethical violations
as we see it now?
 Study subjects were members of vulnerable populations including
institutionalized and mentally disabled persons, prison inmates, and
soldiers (who could not give valid informed consent).

  Individuals were intentionally infected with pathogens that could

cause serious illness.

 Deception was used in conducting the experiments.

Source: Thomas R. Frieden and Francis S. Collins, Intentional Infection of Vulnerable Populations in
1946-1948, JAMA, October 11, 2010,
http://jama.ama-assn.org/cgi/content/full/jama.2010.1554v1. Published online Oct 11, 2010; (doi:
10.1001/jama.2010.1554)
JAMA
October 1, 2010

Secretary of State Hillary Rodham Clinton and Secretary of DHHS

Kathleen Sebelius offer a formal apology for the study on the part of the
United States Government calling it abhorrent, unethical, and
reprehensible.
 President Barack Obama
calls Guatemalan President Alvaro
Colom to express his deep regret.

Colom calls it “crimes against

Humanity.”

The President s Commission on Bioethical Issues is asked to find

the facts on the studies in Guatemala and to re-examine protections
for human subjects, especially in international trials and to report
back within the year.
October 2010

 9:00 AM, October 1: Reverby makes sure the synopsis and un-copy
edited article goes up on Reverby faculty page, not her book website

 9:05 AM, October 1: Media coverage is frenzied and world-wide

after DHSS gives embargoed story to Robert Bazell of NBC the night
before (but does not tell Reverby this)

 11:00 AM, October 1:Federal officials hold press conference and

explain apology.

 October 1-November 1: Reverby responses to hundreds of media

requests and emails

 October 11: The directors of the National Institutes of Health and

CDC called the study regrettable and deeply saddening in an
editorial in JAMA.
Presena Libre October 3, 2010, p. 21.
Clinton: Mr. President, I apologize for our government’s inoculating your people with syphilis and gonorrhea.
Short man representing the Guatemalan people: Besides the cold war, the paramilitary groups, the demand for drugs, and
The hate toward immigrants? Prensa Libre, October 2, 2010, p. 18.
 Ethics in Context
 At the time it was not uncommon to use vulnerable populations
in the United States.

 Infecting/inoculating studies had been done before and there

has been media uproar before over infecting syphilis studies
before.

 Deception was seen as possibly normative in the interest of doing

science.

 When this started discussion over codes and regulations, rather

than some normative ethical sense, were just happening.
Nevertheless there is knowledge of ethical actions and behaviors.
Why the Coverage?
• The U.S. does not usually apologize to other
countries, for anything.

• The details are gruesome and involve sex

• The story fits the trope of a Grade B horror film.

Intrepid explorer is now an historian and
seemingly single doctor is the monster?

• There is underlying mistrust of medical research

and the government’s power combined,
especially when this happens by the US outside
its borders.

• Concern over the extent of testing/research by

US companies outside our borders
Why then was there an apology?

Need to correct an historical wrong doing

Need to get ahead of the story before it was picked

up by the media; knowledge that this was not done
with the study in Tuskegee

Aware that majority of clinical and drug trials are

now being done off shore

Concern that the debate on protecting international

subjects has advanced over the last decade
Some Thoughts about the coverage and its limits

 Cutler and colleagues thought they were doing good science

against a dreadful disease.

 What is the danger that Cutler will be seen as a monster like the
Nazi Dr. Mengele and broader institutional support for his work ignored?

 Should we worry now that the majority of drugs coming into the market
are approved by the FDA based on studies done outside the
United States?

 How do we assess the role of the Guatemalan state in all of this?

 How should the discussion on human subject protections go

forward? Do we need more regulations? Better researcher
training? One world-wide standard?
President’s Commission on Bioethical Issues Begins
Review

Goes through 447 boxes in various archives to obtain more

facts and context on the studies in Guatemala

Sets up international panel to meet on human protections

Holds hearing on March 1, 2011 and hears from experts

and the public

Promises findings by the end of the summer

What is happening right now?

President’ commission review and perhaps proposals for

new regulations?

The lawsuit, under the alien tort statute, has been filed
by 7 Guatemalans but the number in the case is
expected to grow. The firm calls it the “Guatemalan
Tuskegee.”

Media coverage continues since the lawsuit

What do we think the public discourse should be about?

Sources
  Susan M. Reverby, Normal Exposure and Inoculation
Syphilis: A PHS Tuskegee Doctor in Guatemala, 1946–
1948, Journal of Policy History 23 (Winter 2011) 6-28.!
  DHSS, Information on the 1946-1948 USPHS STD
Inoculation Study, http://www.hhs.gov/
1946inoculationstudy/!
  Susan M. Reverby, After the Media Frenzy, Preventing
another Guatemala, Bioethics Forum, October 6, 2010,
http://www.thehastingscenter.org/Bioethicsforum/
Post.aspx?id=4919&blogid=140!
  Susan M. Reverby, Examining Tuskegee: The Infamous Syphilis
Study and its Legacy (Chapel Hill: University of North
Carolina Press, 2009) and http://
www.examiningtuskegee.com!
  Susan M. Reverby, ed. Tuskegee s Truths: Rethinking the
Tuskegee Syphilis Study (Chapel Hill: University of North
Carolina Press, 2000).!
Appendix
 1950s to 1960s

1950
NIH Clinical Center requires informed consent for its studies
1953- 1954
Sing Sing Prison syphilis inoculation study
1956- 1972
Hepatitis studies at Willowbrook State School for the Retarded
1960
NIH Clinical Center requires independent ethical review for its studies
1962
Kefauver-Harris drug amendments
1963
Jewish Hospital cancer study
1964
World Medical Association Declaration of Helsinki
1966
US Surgeon General policy statement on human subjects research (IRB origin)
 1970s to 1980s
1971
NIH Office for Protection from Research Risks established
1974-1978
National Commission for the Protection of Human Subjects
1974
HHS regulations for human subjects research
1975
CDC Office of Human Research Protections established
1978-1983
President s Commission for the Study of Ethical Problems
1979
Belmont Report released
1981
HHS 45 CFR 46 and Food and Drug Administration 21 CFR 50, 56 regulations
published
1985
NIH Clinical Center Bioethics Program founded
 1990s
1991
45 CFR 46 (Common Rule) adopted
1993
CIOMS guidelines released
1994
Presidential apology for secret radiation experiments
1995
World Health Organization Guidelines for Good Clinical Practice
1996-2001
National Bioethics Advisory Commission
1996
Department of Bioethics established at NIH Clinical Center
1997
Presidential apology for Tuskegee
1998
NIH support for bioethics training and research expanded
1999
NIH support for international research and ethics training
 2000s

2000
World Health Organization operational guidelines for ethics committees

2001-2009
President s Council on Bioethics

2002
Secretary s Advisory Committee on Human Research Protections

2005
UNESCO Universal Declaration on Bioethics and Human Rights

2009
Executive order to create Presidential Commission for the Study of Bioethical
Issues