How to Justify the Use of Human Guinea Pigs

Now that coverage of the Ebola outbreak in Africa has basically disappeared from the world's media and, with revelations that pharmaceutical companies were expediting the development of an anti-Ebola vaccine, I recalled a time in American history where there was a relatively urgent need to develop a treatment for a disease that that had no real cure at the time.  Here is the story of how the American government justified using human testing to develop a cure for a disease and which country was selected for this honour.  

Between 1946 and 1948, the United States government through the National Institutes of Health and under the guidance of Dr. John C. Cutler undertook at study that was looking for new ways to prevent sexually transmitted diseases (STDs) including syphilis, gonorrhoea and chancroid.  As background, in 1947, it was believed that an experiment with rabbits that intentionally exposed them to syphilis followed by an injection of penicillin within a few days could prove be a panacea to preventing the spread of the disease, if only the experiment could be undertaken on humans.  Prior to the 1940s, the treatment for syphilis was to have men urinate, wash with soap and water and then receive an injection of silver proteinate into their penises followed by rubbing calomel ointment over their penis and pubic regions to control and prevent syphilis.  This methodology was not terribly effective.  Other methods included the use of salvarsan, an arsenic-based compound which proved to be complicated and sometimes toxic.  By 1938, sulfanilamide became the drug of choice for reliably curing gonorrhoea.  Unfortunately, it was still expected that there would be 350,000 new cases of gonorrhoea in the Armed Forces during the Second World War which would result in 7,000,000 lost man days per year and a cost of treatment equivalent to $440 million today.

In order to test the effectiveness of penicillin over a shortened timeframe, it was necessary to use human test subjects.  It is under this background that Dr. Cutler's Guatemala experiment took place.  In the first phase of this experiment, female commercial sex workers in Guatemala (commercial sex was legal in Guatemala at the time) were infected with gonorrhoea or syphilis and then allowed to have unprotected sex with prisoners, mental hospital patients and soldiers.  This phase of the experiment was unsuccessful since few of the men involved became infected.  In the next phase, a total of 1308 research subjects were intentionally exposed to the three STDS.  These included soldiers, prisoners and mental hospital patients, four of whom are shown on this screen capture:

  

The subjects were directed inoculated with the agents; gonorrhoea was directly injected into the urethra using a toothpick swab inserted 1/2 inch into the urethra, chancroid was injected into the skin and syphilis was introduced by skin injection and by exposing the foreskin of the penis to the infectious agent.  In seven cases, women were exposed to syphilis through the injection of the bacteria directly into the spinal fluid through a cisternal puncture.  Scientists also wanted to better understand whether syphilis could penetrate the mucous membranes of the digestive system; in these cases, subjects swallowed a mixture of testicular tissue, fluid containing syphilis and distilled water.  In each case, the subjects were not informed of the purpose of the study and did not consent to being part of a study.  Here is a table summarizing the methods used to introduce STDs to the subjects involved in the study:

  

Records show that 678 subjects that contracted gonorrhoea and chancroid received treatment, however, research suggests that some of the subjects infected with syphilis were prescribed either no treatment or partial treatment.  The records do not reflect whether or not the infected commercial sex workers were treated.  

In addition to the 1308 research subjects, 5128 subjects including soldiers, prison inmates, psychiatric patients (a total of 642 patients), children (a total of 1384 between the ages of 1 and 18 years from both orphanages and the highland area of Guatemala), leprosy patients and American Air Force personnel located at the U.S. base in Guatemala were the targets of diagnostic testing which included blood tests and lumbar punctures to improve the tools available to accurately diagnose antibodies that indicated exposure to syphilis.  These continued until 1953.

In all, between February 1947 and October 1948, Dr. Cutler undertook 32 gonorrhoea experiments, 17 syphilis experiments and one chancroid experiment as shown on this table:

During the course of the experiments, 83 subjects died, however, the relationship between the experiment and the deaths is unclear.  Dr. Cutler attributed the "steady loss of patients by death" to tuberculosis.

According to the U.S. Department of Health and Human Services (HHS), the following ethical breaches took place:

1.) The use of subjects who were part of a highly vulnerable population.

2.) Research took place without valid and informed consent of the subjects involved.

3.) Deception was used by those who conducted the study.

The Guatemala travesty was discovered during research on the Tuskegee Study of Untreated Syphilis by Professor Susan Reverby, a 1943 - 1944 study that left nearly 400 African American males in Alabama with syphilis untreated for nearly 30 years with the United States government observed the progress of their infections. 

The HHS claims that:

"Such abuses could not occcur today in research funded or conducted by the U.S. government. A series of safeguards established over the past 40 years provide protection for human participants, whether in the United States or overseas, in medical research from these types of abuses."

That said, here is a critical paragraph from the "Ethically Impossible" report released by the Presidential Commission for the Study of Bioethical Issues in 2011: 

"While research is sometimes still done with vulnerable populations, using deliberate exposure and infection, and without informed consent, such studies have to be carefully justified, reviewed, and approved often with additional protections added."

One has to question whether, in the haste to develop a human vaccine for Ebola particularly if the outbreak gains strength in the developed world, exceptions to the "research rules" for uninformed consent and the use of vulnerable populations (i.e. African men and women) might be found in the interest of both drug company profits and expedited vaccine product development.

Ebola and the Challenges Facing the Medical Community

An article in the American College of Physicians' Annals of Internal Medicine gives us an idea of how challenging it will be for medical facilities to care for Ebola patients in North America.

Let's get a bit of background first.  Scientists have developed the Biohazard Safety Level protocols to assist medical professionals and researchers who are working with hazardous materials.  There are four biohazard levels, BSL-1, BSL-2, BSL-3 and BSL-4 as shown on this diagram:

Here is a summary of each level:

BSL-1: If you work in a lab that is designated a BSL-1, the microbes there are not known to consistently cause disease in healthy adults and present minimal potential hazard to laboratorians and the environment. An example of a microbe that is typically worked with at a BSL-1 is a nonpathogenic strain of E. coli.

Personal Protective Equipment (PPE) includes lab coats, gloves and eye protection.

Facilities must have a sink for hand washing and have doors to separate the working space from the rest of the facility.

BSL-2:  BSL-2 builds upon BSL-1. If you work in a lab that is designated a BSL-2, the microbes there pose moderate hazards to laboratorians and the environment. The microbes are typically indigenous and associated with diseases of varying severity. An example of a microbe that is typically worked with at a BSL-2 laboratory is Staphylococcus aureus.

PPE: includes lab coats, gloves and eye protection (i.e. face shields) as needed.

Facilities must have self-closing doors and a sink and eyewash must be readily available.  Procedures are performed within a biological safety cabinet and an autoclave or other decontamination method is used to ensure proper disposal of waste.

BSL-3: BSL-3 builds upon the containment requirements of BSL-2. If you work in a lab that is designated BSL-3, the microbes there can be either indigenous or exotic, and they can cause serious or potentially lethal disease through respiratory transmission. Respiratory transmission is the inhalation route of exposure. One example of a microbe that is typically worked with in a BSL-3 laboratory is Mycobacterium tuberculosis, the bacteria that causes tuberculosis.

PPE: May include respirators and the aforementioned equipment including full body coverage.  Personnel are under medical surveillance and may receive immunization for the microbes that they work with.

Facilities must have controlled and restricted access and have hands-free sinks and eyewash equipment.  Exhaust air cannot be recirculated and air must be drawn into the laboratory from clean areas and exhausted outwards.  Entrance to the lab is through two sets of self-closing and locking doors.

BSL-4: BSL-4 builds upon the containment requirements of BSL-3 and is the highest level of biological safety. There are a small number of BSL-4 labs in the United States and around the world. The microbes in a BSL-4 lab are dangerous and exotic, posing a high risk of aerosol-transmitted infections. Infections caused by these microbes are frequently fatal and without treatment or vaccines. Two examples of microbes worked with in a BSL-4 laboratory include Ebola and Marburg viruses.

PPE: If a Class III biological safety cabinet is not available, laboratory personnel must wear a full body, air-supplied positive pressure suit as shown in this picture:

You can readily see how this type of PPE would not be widely available in most hospitals and medical centers around the world.  Clothing must be changed before entering and personnel must shower upon exiting.  All materials must be decontaminated before exiting the facility.

Facilities must be in a separate building or in an isolated or restricted zone of the building.  The laboratory has a dedicated supply of air, vacuum lines and decontamination systems.

You'll note that scientists working with Ebola require a BSL-4 level facility.

Here is a chart summarizing of all four biohazard levels:

  

 If you want to see all of the details of what protocols are required for each of the Biohazard Safety Hazard levels, here is a link to the Centres for Disease Controls (CDC)Laboratory Biosafety Level Criteria document.

Now, back to the subject of this posting.  The authors noted that the CDC has developed a hospital preparedness checklist for hospitals dealing with Ebola.  The CDC believes that Ebola patients can be cared for in a conventional medical facility by using barrier methods and that high-level containment care (HLCC) such as that offered at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) is not necessary (it has since been decommissioned).  Currently, there are four facilities in the United States that offer a higher level of containment than a conventional hospital isolation room:

1.) Emory University Hospital in Atlanta, Georgia

2.) University of Nebraska Medical Centre in Omaha, Nebraska

3.) St. Patrick's Hospital in Missoula, Montana

4.) National Institutes of Health Clinical Centre in Bethesda, Maryland

The authors state that staff in conventional medical centres are learning that dealing with patients infected with an Ebola virus presents significant challenges.  It is impossible to rule out human error such as needlesticks or cuts from sharps.  Hospitals must be prepared for the following:

1.) Provide a means of triaging potential Ebola patients safely since these patients can present themselves to the facility unannounced.

2.) Entry and movement of Ebola patients through the facility.

3.) A location for the safe donning and removal of personal protective equipment.

4.) Handling of laboratory specimens.

5.) Disposal of all waste associated with Ebola patients.

6.) Cleaning up of spills and bodily waste materials.

The authors emphasize that there is a significant increase in the risk of infection when taking off potential contaminated personal protective equipment and that there is no room for error.

The authors recommend that, since it will be very difficult and prohibitively expensive to maintain a nationwide state of high alert for a long period to time, a network of regional referral centers that are tied to BSL-4 laboratories should be developed.  Patients that present with Ebola would be transferred to these major medical centres that have the ability to provide BSL-4 security as well as the day-to-day care that Ebola patients require without interfering with their normal operations.

As we can see, the complexity of handling and managing patients with Ebola would be well beyond the scope of most of the hospitals in the United States, Canada and the remainder of the developed world let alone the medical facilities in the world's developing nations.  With outbreaks of deadly disease being relatively rare in our lifetimes, while practice may make perfect, there has been very little opportunity for the vast majority of the medical community to practice the skills necessary to keep a deadly virus from spreading.

Aerosols and Ebola - How Far Can Ebolavirus Spread?

In searching for information on Ebola, I happened to find this rather old (1995) article on the transmission of Ebola (Zaire), the species of Ebola that is responsible for the current outbreak in Africa and the cases in North America.  The article by Dr. N Jaax, a veterinarian and his colleagues, was released December 1995 in "The Lancet", a renowned medical periodical, and provided a glimpse of how the Ebola virus could be transmitted through the air, a contrast to the widely held and much propagated theory that Ebola is spread only through direct contact with an infected person's bodily fluids.

The authors begin by noting that the the route of infection for human filovirus exposures is unknown. As we've been repeatedly told, close contact with vomit, blood, diarrhea, tissue and improper medical hygiene are the main routes by which Ebola spreads from person to person.  The importance of aerosols, a system of liquid or solid particles that are suspended in air, has been little studied in the transmission of Ebola. 

The authors reported that a secondary transmission of Ebola took place in a laboratory where both experimentally infected and non-infected (the control group) rhesus monkeys were held.  The monkeys were part of an experiment that was design to evaluate the therapeutic value of alpha-interferon in the fight against Ebola (Zaire).  The two groups of monkeys had no physical contact with each other, in fact, they were housed in stainless steel cages located approximately 3 metres or 10 feet from each other.   The first of the inoculated monkeys died 7 days after infection and the last died 13 days after infection.  At that point, the control group monkeys appeared to be entirely normal with no signs of hemorrhagic fever.   Two of the three control monkeys became infected and died from the Ebola virus; the first died 10 days after the last experimentally infected monkey died (22 days after the inoculation of the experimentally infected monkeys) and the second died the following day.  Necropsies showed that the control monkeys had large amounts of Ebola virus present throughout their organs, including the liver, spleen, lymph nodes, adrenal gland, small intestine, kidneys and lungs.

The scientists involved were extremely cautious about the procedures used during this experiment; cages were cleaned using Lysol and low-pressure water to minimize the creation of aerosols.  All cleaning procedures were carried out first on the cages containing the control animals to ensure that the Ebola virus was not inadvertently transmitted to them.  As well, all blood testing and viral swab sampling were performed first on the control monkeys, again, to ensure that there was no cross contamination.  The laboratory procedures used in this experiment had been used by the same lab in other experiments and had successfully prevented the transmission of Ebola and Marburg viruses to uninfected animals.

Here is the authors' conclusion:

"The exact mode of transmission to the control monkeys cannot be absolutely determined, although the pattern of pulmonary (lung) antigen staining in one of the control monkeys was virtually identical to that reported in experimental Ebola virus aerosol transmission of the disease via infectious droplets.

While airborne transmission of Ebola hemorrhagic fever has not been documented in humans, only limited tissues have been available for complete virological and histopathological examinations.  Our present findings emphasize the advisability of at-risk personnel employing precautions to safeguard against ocular, oral and nasopharyngeal exposure to the virus....These data also suggest potential avenues of exploration regarding the routes of infection for index human cases of Ebola fever, which remains a mystery."  (my bold)

Given my previous posting on the airborne spread of Ebola over a 15 centimetre or 6 inch gap between infected and non-infected laboratory animals, I found it rather stunning that nearly 20 years ago, scientists had observed that Ebola (Zaire) appeared to spread over a 3 metre or 10 foot gap between infected and non-infected animals.  If the aerosol theory is correct and is responsible for at least some of the secondary Ebola infections in Africa, it will be almost impossible to control given how many times daily humans are in contact that is closer than 10 feet, particularly in a hospital or even an urban setting.

Should you happen to want to read the entire document, it was a bit difficult to find more than just the abstract so here is a screen capture of all three pages:

  

In case you were hopeful, the study also proved that interferon was ineffective at controlling Ebola.