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The 10 Cruelest Human Experimentation Cases in History

“First, do no harm,” is the oath taken by physicians the world over. And this has been the case for centuries now. For the most part, these men and women of science stay faithful to this oath, even defying orders to the contrary. But sometimes they not only break it, they do so in the worst way imaginable. There have been numerous instances of doctors and other scientists going way beyond the limitations of what’s moral or ethical in the name of ‘progress’. They have used humans as experimental guinea pigs for their tests.

In many cases, the test subjects were either kept in ignorance about what an experiment involved or they were simply in no position to offer their resistance or consent. Of course, it may well be the case that such dubious methods produced results. Indeed, some of the most controversial experiments of the past century produced results that continue to inform scientific understanding to this day. But that will never mean such experiments will be seen as just. Sometimes, the perpetrators of cruel research lose their good names or reputations. Sometimes they are prosecuted for their attempts to ‘play God’. Or sometimes they just get away with it.

You might want to brace yourself as we look at the ten weirdest and cruelest human experiments carried out in history:

Dr. Shiro Ishii and Unit 731

During World War II, Imperial Japan committed a number of crimes against humanity. But perhaps few were crueler than the experiments that were conducted at Unit 731. Part of the Imperial Japanese Army, this was a super-secret unit dedicated to undertaking research into biological and chemical weapons. Quite simply, the Imperial authority wanted to build weapons that were deadlier – or just crueler – than anything that had gone before. And they weren’t opposed to using human guinea pigs to test their creations.

Based in Harbon, the biggest city of Manchuko, the part of north-east China that Japan made its puppet state, Unit 731 was constructed between 1934 and 1939. Overseeing its construction was General Shiro Ishii. Though he was a medical doctor, Ishii was also a fanatical soldier and so he was happy to set his ethics aside in the name of total victory for Imperial Japan. In all, it’s estimated that as many as 3,000 men, women and children were used as forced participants in the experiments conducted here. For the most part, the horrific tests were carried out on Chinese people, though prisoners-of-war, including men from Korea and Mongolia, were used.

For more than five years, General Ishii oversaw a wide range of experiments, many of them of dubious medical value to say the least. Thousands were subjected to vivisections, usually without anaesthetic. Often, these were fatal. Countless types of surgery, including brain surgery and amputations, were also carried out without anaesthetic. At other times, inmates were injected directly with diseases such as syphilis and gonorrhoea, or with chemicals used in bombs. Other twisted experiments included tying men up naked outside and observing the effects of frostbite, or simply starving people and seeing how long they took to die.

Once it was clear Japan was going to lose the war, General Ishii tried to destroy all evidence of the tests. He burned down the facilities and swore his men to silence. He needn’t have worried. Senior researchers from Unit 731 were granted immunity by the U.S. In exchange, they contributed their knowledge to America’s own biological and chemical weapons programs. For decades, any stories of atrocities were dismissed as ‘Communist Propaganda’. In more recent years, the Japanese government has acknowledged the Unit’s existence as well as its work, though it maintains most official records have been lost to history.

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“The Little Albert Experiment”

After many months observing young children, John Hopkins University psychologist Dr. John B. Watson concluded that infants could be conditioned to be scared of non-threatening objects or stimuli. All he needed was first-hand proof. Since it was 1919 and experimental ethics were nowhere near as strict as they are today, Watson, along with his graduate student Rosalie Rayner, set about designing an experiment to test their theory. Thanks to their connections at the Baltimore hospital, they were able to find a young baby, named ‘Albert’, and ‘borrow’ him for the afternoon. While Albert’s mother might have consented to her son helping out scientific research, she had no idea what Watson was actually planning.

The young Albert was just nine months old when he was taken from a hospital and put to work as Watson’s guinea pig. At first, Watson carried out a series of baseline tests, to see that the child was indeed emotionally stable and at the accepted stage of development. But then the tests got creepier. Albert was shown several furry animals. These included a dog, a white rat and a rabbit. Watson would show these toys to Albert while at the same time banging a hammer against a metal bar. This was repeated a number of times. Before long, Albert was associating the sight of the furry animals with the fear provoked by the loud, unpleasant noise. Indeed, within just a short space of time, just seeing the furry rat could distress the child.

Watson noted at the time: “The instant the rat was shown, the baby began to cry. Almost instantly he turned sharply to the left, fell over on [his] left side, raised himself on all fours and began to crawl away so rapidly that he was caught with difficulty before reaching the edge of the table.” The scientist and his research partner had achieved their goal: they had proof that, just as in animals, classical conditioning can be used to influence or even dictate emotional responses in humans. Watson published his findings the following year, in the prestigious Journal of Experimental Psychology .

Even at the time, Watson’s methods were seen as unethical. After all, isn’t a doctor supposed to ‘do no harm’? What’s more, Watson never worked with Little Albert again, so he wasn’t able to reverse the process. But still, the results were heralded as a breakthrough in our understanding of popular psychology. Notably, Watson recorded the Little Albert Experiment, and the videos can be seen online today. And, for what it’s worth, most experts now agree that, though he would have most likely feared furry objects for a short spell of time during his childhood, Little Albert probably lost the association between cute toys and loud noises.

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The “Monster” Study

These days, any tests carried out on children are subject to strict ethical rules and guidelines. This wasn’t the case back in the 1930s, however. So, when Wendell Johnson, a speech pathologist at the University of Iowa, wanted to carry out research on young participants, his institution was happy to oblige. Along with Mary Tudor, a grad student Johnson was supervising, work began in 1939. Over the next few years, dozens of kids would be subject to speech-related tests, with the effects of the experiment lasting for decades.

The purpose of the research sounded noble enough: Johnson wanted to see how a child’s upbringing affects their speech. In particular, he was fascinated by stuttering and determined to see what made one child stutter, yet another speak fluently. Thankfully, a local orphanage was able to ‘supply’ Johnson and Tudor with 22 children for them to work with. All of the young participants spoke without a stutter when they arrived at the University of Iowa labs for the first time. They were then divided into two equal groups, and the experiment got underway.

Both groups were asked to speak for the researchers. How they were treated, however, was completely different. In the first group, all of the children received positive feedback. They were praised for their fluent speech and command of the English language. The second group received the opposite kind of treatment. They were ridiculed for their inability to speak like adults. Johnson and Tudor would listen carefully for any little mistakes, and above all for any signs of stuttering, and criticize the children harshly for them.

Johnson’s methods shocked his academic peers. Not that they would have been so surprised. As a young researcher at the University of Iowa, he gained a reputation for experimenting with shock tactics. For instance, as a postgraduate student himself, Johnson would work with his colleagues trying to cure his own stutter, even electrocuting himself to see if that made a difference. But still, inflicting deliberate cruelty on children was seen as a step too far. As such, the Iowan academics nicknamed Johnson’s 1939 research ‘The Monster Study’. And the name was just about the only thing of significance it gave us.

With the University of Iowa keen to distances itself from news of human experimentation being carried out by the Nazis in war-torn Europe, they hushed-up the Monster Study. None of the findings were ever published in any academic journal of note. Only Johnson’s own thesis remains. The effects were clear, however. Many of the children in the second group went on to develop serious stutters. Some even had serious speech problems for the rest of their lives. The university finally acknowledged the experiment in 2001, apologising to those involved. Then, in 2007, six of the original orphan kids were awarded almost $1 million in compensation for the psychological impact Johnson’s work had on them.

Interestingly, however, while the methods used for the Monster Study have widely been condemned as being cruel and simply indefensible, some have argued that Johnson may have been onto something. Certainly, Mary Tudor said before her death that she and her research partner might have made serious contributions to our understanding of speech and speech pathology had they been allowed to publish their work. Instead, the experiment is now shorthand for bad science and a complete lack of ethics.

The Stanford Prison Experiment

Off all the ill-advised – and indeed, cruel – experiments North American universities have carried out over the decades, none is more infamous than the Stanford Prison Experiment. It’s so famous, in fact, that movies have been made based on the experiment which took place at Stanford University for one week in August 1971. Furthermore, while undoubtedly cruel, its findings are still used to inform popular understanding of psychological manipulation. Moreover, the behaviour of the participants involved is often held up as a warning about what can happen if humans are given power without accountability.

The experiment was led by Professor Phillip Zimbrano. As a psychologist, he was eager to see whether abuse in prisons can be explained by the inherent psychological traits of both guards and prisoners. Given the topic, he received funding from the U.S. Office of Naval Research. Funding in hand, Zimbrano set about recruiting participants. This turned out to be no problem at all, as a number of Stanford students volunteered to take part. Zimbrano then appointed some of the volunteers as guards and the others were designated as prisoners. The experiment could begin.

In the basement of the university’s psychology department, Zimbrano had built a makeshift ‘prison’. In all, 12 prisoners were kept here in small cells, while 12 guards were assigned a different part of the basement. While the prisoners had to endure tough conditions, the guards enjoyed comfortable, furnished quarters. The participants were also dressed for their parts, with the guards given uniforms and wooden batons. They were also kitted out with dark sunglasses so they could avoid eye contact with the people they were tasked with guarding.

Within 24 hours, any semblance of calm had gone. The prisoners started to revolt and the guards started to react. Special cells were set up to give well-behaving prisoners preferential treatment. The guards – who were barred from actually physically hitting their charges – started to use psychological methods to keep prisoners down. They would deny them food or put prisoners in darkened cells. Sleep was also denied to the prisoners. Within six days, Zimbrano agreed to halt the experiment. He did, at least, have more than enough evidence – some of it filmed – to draw on when making his conclusions.

Professor Zimbrano noted that around one third of the guards – again, young men taken randomly from the Stanford student population – exhibited genuine sadistic tendencies. At the same time, most of the inmates were seen to ‘internalise’ their roles. They took on the mentality of prisoners. While they could have left at any time, they instead gave up and became weak and passive. In the end, the experiment received, and continues to receive, criticism for the harsh methods used. Nevertheless, the findings of the Stanford Prison Experiment actually changed the way U.S. prisons are run and they are often held up as proof that most people can inflict cruelty and suffering on another human being if they are given a position of power and ordered to do so.

The South African ‘Aversion Project’

In Apartheid-era South Africa, national service was compulsory for all white males. At the same time, homosexuality was classed as a crime. Inevitably, therefore, any gay men who found themselves called into service were in for a tough time. But it wasn’t just name-calling or casual discrimination they had to contend with. Many were subjected to cruel experiments. The so-called ‘Aversion Project’, run throughout the 1970s and then the 1980s, was aimed at ‘treating’ homosexuals. As well as psychological treatments, it also used physical ‘treatments’, many of which would rightly be regarded as torture.

The project first really got started in 1969, with the creation of Ward 22. The creepily-named ward was part of a larger military hospital just outside of Pretoria and was designed to treat mentally-ill soldiers. For the unit chief Dr Aubrey Levin, this including homosexuals, regarded as unstable, or even ‘deviants’. For the most part, the doctor was determined to prove that electric shock therapy and conditioning could ‘cure’ the patients of their desires. Hundreds of men were electrocuted, often while being forced to look at pictures of gay men. The electric current would then be turned off and pictures of naked women shown instead in the hope that this would alter the mindset.

Inmates subjected to such experimental treatment would sometimes be tested, given temptations to see if they really were ‘cured’. Persistent ‘offenders’ were given hormone treatments, almost always against their will, and many were even chemically castrated. Even by the middle of the 1970s, when numerous, more ethical, studies had proven that ‘conversion therapies’ could change a person’s sexuality, Ward 22 carried on with its work. In fact, in only ended with the fall of the apartheid regime. To the very end of the project, Dr Levin maintained that all the men he treated were volunteers and asked for his help. Many of his peers disagreed, as did a judge, who sentenced him to five years in prison in 2014.

Project 4.1

On March 1, 1954, the United States carried out Castle Bravo , testing a nuclear bomb on the Bikini Atoll, in the middle of the Pacific Ocean. The test not only went without a hitch, it actually went better than expected. The yield produced by the bomb was much higher than scientists had anticipated. At the same time, the weather conditions in this part of the Pacific turned out to be different to what had been predicted. Radiation fallout from the blast was blown upwind, towards the Marshall Islands. But, instead of alerting the islanders to the danger, the project heads sensed an opportunity. How many times would they be able to see the affect of radiation fallout on a population for real?

Making the most of the opportunity, the American scientists simply sat back an observed. That is, they watched innocent people be affected by the fallout of an American nuclear bomb. Over the next decade, the project observers noted an upturn in the number of women on the Marshall Islands suffering miscarriages or stillbirths. But then, after ten years or so, this spike ended. Things seemingly returned to normal, and so scientists were unable – or unwilling – to make any formal conclusions. But then, things started to go downhill again.

At first, children on the Marshall Islands were observed to be growing less than would be expected. But then, it became clear that not only were they suffering from stunted growth, but a higher-than-expected proportion of youngsters were developing thyroid cancer. What’s more, by 1974, the data was showing that one in three islanders had developed at least one tumor. Later analysis, published in 2010, estimated that around half of all cancer cases recorded on the Marshall Islands could be attributed to the 1954 nuclear test, even if people never displayed any obvious signs of radiation poisoning in the immediate aftermath of the explosion.

Given that the initial findings of Project 4.1 as it was known were published in professional medical journals as early as 1955, the American government has never really denied that the experiment took place. Rather, what has been, and continues to be contested, is whether the U.S. actually knew that the islands would be affected before they carried out the test. Many on the Marshall Islands believe that Project 4.1 was premeditated, while the American authorities maintain that it was improvised in the wake of the explosion. The debate continues to rage.

The Tuskegee Experiments

For four decades, African-American men in Macon County, Alabama, were told by medical researchers that they had ‘bad blood’. The scientists knew that this was a term used by sharecroppers in this part of the country to refer to a wide range of ailments. They knew, therefore, that they wouldn’t question the prognosis. And neither would they raise any concerns or questions when the same researchers gave them injections. Which is how doctors working on behalf of the U.S. Public Health Service (PHS) were able to look on as hundreds of men went mad, blind or even died as a result of untreated syphilis.

When the experiment began back in 1932, there was no known cure for syphilis. As such, PHS researchers were determined to make a breakthrough. They went to Tuskegee College in Alabama and enlisted their help. Together, they enlisted 622 African-American men, almost all of them very poor. Of these men, 431 had already contracted syphilis prior to 1932, with the remaining 169 free from the disease. The men were told that the experiment would last for just six years, during which time they would be provided with free meals and medical care as doctors observed the development of the disease.

In 1947, penicillin became the recommended treatment for syphilis. Surely the doctors would give this to the men participating in the Tuskegee Experiment? Not so. Even though they knew the men could be cured, the PHR workers only gave them placebos, including aspirin and even combinations of minerals. With their condition untreated, the men slowly succumbed to syphilis. Some went blind, others went insane, and some died within a few years. What’s more, in the years after 1947, 19 syphilitic children were born to men enrolled in the study.

It was only in the mid-1960s that concerns started to be raised about the morality of the experiment. San Francisco-based PHS researcher Peter Buxton learned about what was happening in Alabama and raised his concerns. However, his superiors were unresponsive. As a result, Buxton leaked the story to a journalist friend. The story broke in 1972. Unsurprisingly, the public were outraged. The experiment was halted immediately, and the Congress inquiries began soon after. The surviving participants, as well as the children of those men who had died, were awarded $10 million in an out-of-court settlement. Finally, in 1993, President Bill Clinton offered a formal and official apology on behalf of the U.S. government to everyone affected by the experiment.

Project MK-Ultra

Though they had the Bomb, in the 1950s, the CIA were still determined to enjoy every advantage over their enemies. To achieve this, they were willing to think outside of the box. Perhaps the best example of this was MK-Ultra, a top-secret project where the CIA attempted to alter brain function and explore the possibility of mind control. While much of the written evidence, including files and witness testimonies, were destroyed soon after the experiments were brought to an end, we do know that the project involved a lot of drugs, some sex and countless instances of rule bending and breaking.

Project MK-Ultra was kick-started by the Office of Scientific Experiments at the start of the 1950s. Central to the project was determining how LSD affects the mind – and, more importantly, whether this could be turned to America’s advantage. In order to learn more, hundreds, perhaps even thousands of individuals, were given doses of the drug. In almost all cases, they were given LSD without their explicit knowledge or consent. For example, during Operation Midnight Climax in the early 1960s, the CIA opened up brothels. Here, the male clients were dosed up with LSD and then observed by scientists through one-way mirrors.

The experiments also included subjecting American citizens to sleep deprivation and hypnosis. Not all of the tests went plainly. Several people died as a direct result of Project MK-Ultra, including a US Army biochemist by the name of Frank Olsen. In 1953, the scientist was given a dose of LSD without his knowledge and, just a week later, died after jumping out of a window. While the official reason of his death was recorded as suicide, Olsen’s family have always maintained that he was effectively killed by the CIA.

When President Gerald Ford launched a special Commission on CIA activities in the United States, the work of Project MK-Ultra came to light. Two years previously, however, the-then Director of the CIA, Richard Helms, had ordered all files relating to the experiments to be destroyed. Witness testaments show that around 80 institutions were involved in the experiments, with thousands of people given hallucinogenic drugs, usually by CIA officers with no medical background. And so, in the end, was it all worth it? The CIA has acknowledged that the experiments produced nothing of real, scientific value. Project MK-Ultra has, however, lived on in the popular imagination and has inspired numerous books, video games and movies.

Guatemalan Syphilis Experiment

For more than two years in the middle of the 20 th century, the United States worked directly with the health ministries of Guatemala to infect thousands of people with a range of sexually transmitted diseases, above all syphilis. Since they wanted to do this without the study subjects knowing about it – after all, who would give their consent to being injected with syphilis? – it was decided that the experiment should take place in Guatemala, with soldiers and the most vulnerable members of society to serve as the guinea pigs.

The Guatemalan Syphilis Experiment (it was not given an official codename or even a formal project title) began in 1946. It was headed up by John Charles Cutler of the US Public Health Service (PHS). Despite being a physician himself, Cutler was happy to overlook the principle of ‘First, do no harm’ in order to carry out his work. Making use of local health clinics, he tasked his staff with infecting around 5,500 subjects. Most of them were soldiers or prisoners, though mental health patients and prostitutes were also used to see how syphilis and other diseases affect the body. Children living in orphanages were even used for the experiments.

In all cases, the subjects were told they were getting medication that was good for them. And, while all subjects were given antibiotics, an estimated 83 people died. In 1948, with the wider medical community hearing rumors of what was being done in Central America, and with the American government wary of the potential fallout, the experiments were brought to an abrupt end. Cutler would go on to carry out similar experiments in Alabama, though even here he stopped short of actually infecting his subjects with life-threatening diseases.

It was only in 2010, however, that the United States government issued a formal apology to Guatemala for the experiments it carried out in the 1940s. What’s more, President Barack Obama called the project “a crime against humanity”. That didn’t mean that the victims could get compensation, however. In 2011, several cases were put forward but then rejected, with the presiding judge noting that the U.S. government could not be held liable for actions carried out in its name outside of the country. A $1 billion lawsuit against the John Hopkins University and against the Rockefeller Foundation is still open.

Mengele’s Twins

A world at war gave the Nazi regime the ideal cover under which they would carry out some of the most horrific human experiments imaginable. At Auschwitz concentration camp, Dr Josef Mengele made full use of the tens of thousands of prisoners available to him. He would carry out unnecessarily cruel and unusual experiments, often with little or no scientific merit. And, above all, he was fascinated with twins. Or, more precisely, with identical twins. These would be the subjects of his most gruesome experiments.

Mengele would personally select prospective subjects from the ramps leading off the transport trains at the entrance to the concentration camp. Initially, his chosen twins were provided with relatively comfortable accommodation, as well as more generous rations than the rest of the inmate population. However, this was just a temporary respite. Mengele’s experiments were as varied as they were horrific. He would amputate one twin’s limbs and then compare the growth of both over the following days. Or he would infect one twin with a disease like typhoid. When they died, he would kill the healthy twin, too, and then compare their bodies.

Gruesomely, the records show that on one particularly bloody night, Mengele injected chloroform directly into the heart of 14 sets of twins. All died almost immediately. Another infamous tale tells of Mengele trying to create his own conjoined twins: he simply stitched two young Romani children back-to-back. They both died of gangrene after several long and painful days. Mengele also had a team of assistants working for him, and they were no less cruel.

Nobody will ever know just how many children or adults were victims of Mengele’s experiments. Despite being meticulous record keepers, the Nazis kept some things secret. Tragically for his victims and their relatives, Mengele never faced justice for his actions. He was smuggled out of Europe by Nazi sympathisers at the end of the war and lived for another 30 years, in hiding, in South America.

Where did we find this stuff? Here are our sources:

“Unmasking Horror: A special report.; Japan Confronting Gruesome War Atrocity”. Nicholas D. Kristof, The New York Times, 1995.

“Little Albert regains his identity”. American Psychology Association, 2010.

“Unit 731: Japan discloses details of notorious chemical warfare division”. Justin McCurry, The Guardian, April 2018.

“The Stuttering Doctor’s ‘Monster Study'”. Gretchen Reynolds, The New York Times, March 2003.

“The Real Lesson of the Stanford Prison Experiment” . Maria Konnikova, The New Yorker, June 2015.

“Gays tell of mutilation by apartheid army” . Chris McGreal, The Guardian, July 2000.

“Nuclear Savage: The Islands of Secret Project 4.1” . The Environment & Society Portal.

“Tuskegee Experiment: The Infamous Syphilis Study” . Elizabeth Nix, History.com, May 2017.

“The secret LSD-fuelled CIA experiment that inspired Stranger Things” . Richard Vine, The Guardian, August 2016.

“Guatemala victims of US syphilis study still haunted by the ‘devil’s experiment'” . Rory Carroll, The Guardian, June 2011.

“Nazi Medical Experiments” . The United States Holocaust Memorial Museum.

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Human Experimentation: An Introduction to the Ethical Issues

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In January 1944, a 17-year-old Navy seaman named Nathan Schnurman volunteered to test protective clothing for the Navy. Following orders, he donned a gas mask and special clothes and was escorted into a 10-foot by 10-foot chamber, which was then locked from the outside. Sulfur mustard and Lewisite, poisonous gasses used in chemical weapons, were released into the chamber and, for one hour each day for five days, the seaman sat in this noxious vapor. On the final day, he became nauseous, his eyes and throat began to burn, and he asked twice to leave the chamber. Both times he was told he needed to remain until the experiment was complete. Ultimately Schnurman collapsed into unconsciousness and went into cardiac arrest. When he awoke, he had painful blisters on most of his body. He was not given any medical treatment and was ordered to never speak about what he experienced under the threat of being tried for treason. For 49 years these experiments were unknown to the public.

The Scandal Unfolds

In 1993, the National Academy of Sciences exposed a series of chemical weapons experiments stretching from 1944 to 1975 which involved 60,000 American GIs. At least 4,000 were used in gas-chamber experiments such as the one described above. In addition, more than 210,000 civilians and GIs were subjected to hundreds of radiation tests from 1945 through 1962.

Testimony delivered to Congress detailed the studies, explaining that “these tests and experiments often involved hazardous substances such as radiation, blister and nerve agents, biological agents, and lysergic acid diethylamide (LSD)....Although some participants suffered immediate acute injuries, and some died, in other cases adverse health problems were not discovered until many years later—often 20 to 30 years or longer.” 1

These examples and others like them—such as the infamous Tuskegee syphilis experiments (1932-72) and the continued testing of unnecessary (and frequently risky) pharmaceuticals on human volunteers—demonstrate the danger in assuming that adequate measures are in place to ensure ethical behavior in research.

Tuskegee Studies

In 1932, the U.S. Public Health Service in conjunction with the Tuskegee Institute began the now notorious “Tuskegee Study of Untreated Syphilis in the Negro Male.” The study purported to learn more about the treatment of syphilis and to justify treatment programs for African Americans. Six hundred African American men, 399 of whom had syphilis, became participants. They were given free medical exams, free meals, and burial insurance as recompense for their participation and were told they would be treated for “bad blood,” a term in use at the time referring to a number of ailments including syphilis, when, in fact, they did not receive proper treatment and were not informed that the study aimed to document the progression of syphilis without treatment. Penicillin was considered the standard treatment by 1947, but this treatment was never offered to the men. Indeed, the researchers took steps to ensure that participants would not receive proper treatment in order to advance the objectives of the study. Although, the study was originally projected to last only 6 months, it continued for 40 years.

Following a front-page New York Times article denouncing the studies in 1972, the Assistant Secretary for Health and Scientific Affairs appointed a committee to investigate the experiment. The committee found the study ethically unjustified and within a month it was ended. The following year, the National Association for the Advancement of Colored People won a $9 million class action suit on behalf of the Tuskegee participants. However, it was not until May 16, 1997, when President Clinton addressed the eight surviving Tuskegee participants and others active in keeping the memory of Tuskegee alive, that a formal apology was issued by the government.

While Tuskegee and the discussed U.S. military experiments stand out in their disregard for the well-being of human subjects, more recent questionable research is usually devoid of obvious malevolent intentions. However, when curiosity is not curbed with compassion, the results can be tragic.

Unnecessary Drugs Mean Unnecessary Experiments

A widespread ethical problem, although one that has not yet received much attention, is raised by the development of new pharmaceuticals. All new drugs are tested on human volunteers. There is, of course, no way subjects can be fully apprised of the risks in advance, as that is what the tests purport to determine. This situation is generally considered acceptable, provided volunteers give “informed” consent. Many of the drugs under development today, however, offer little clinical benefit beyond those available from existing treatments. Many are developed simply to create a patentable variation on an existing drug. It is easy to justify asking informed, consenting individuals to risk limited harm in order to develop new drug therapies for a condition from which they are suffering or for which existing treatments are inadequate. The same may not apply when the drug being tested offers no new benefits to the subjects because they are healthy volunteers, or when the drug offers no significant benefits to anyone because it is essentially a copy of an existing drug.

Manufacturers, of course, hope that animal tests will give an indication of how a given drug will affect humans. However, a full 70 to 75 percent of drugs approved by the Food and Drug Administration for clinical trials based on promising results in animal tests, ultimately prove unsafe or ineffective for humans. 2 Even limited clinical trials cannot reveal the full range of drug risks. A U.S. General Accounting Office (GAO) study reports that of the 198 new drugs which entered the market between 1976 and 1985, 102 (52 percent) caused adverse reactions that premarket tests failed to predict. 3 Even in the brief period between January and August 1997, at least 53 drugs currently on the market were relabeled due to unexpected adverse effects. 4

In the GAO study, no fewer than eight of the drugs in question were benzodiazepines, similar to Valium, Librium, and numerous other sedatives of this class. Two were heterocyclic antidepressants, adding little or nothing to the numerous existing drugs of this type. Several others were variations of cephalosporin antibiotics, antihypertensives, and fertility drugs. These are not needed drugs. The risks taken to develop these drugs by trial participants, and to a certain extent by consumers, were not in the name of science, but in the name of market share.

As physicians, we necessarily have a relationship with the pharmaceutical companies that produce, develop, and market drugs involved in medical treatment. A reflective, perhaps critical posture towards some of the standard practices of these companies—such as the routine development of unnecessary drugs—may help to ensure higher ethical standards in research.

Unnecessary Experimentation on Children

Unnecessary and questionable human experimentation is not limited to pharmaceutical development. In experiments at the National Institutes of Health (NIH), a genetically engineered human growth hormone (hGH) is injected into healthy short children. Consent is obtained from parents and affirmed by the children themselves. The children receive 156 injections each year in the hope of becoming taller.

Growth hormone is clearly indicated for hormone-deficient children who would otherwise remain extremely short. Until the early 1980s, they were the only ones eligible to receive it; because it was harvested from human cadavers, supplies were limited. But genetic engineering changed that, and the hormone can now be manufactured in mass quantities. This has led pharmaceutical houses to eye a huge potential market: healthy children who are simply shorter than average.

Short stature, of course, is not a disease. The problems short children face relate only to how others react to their height and their own feelings about it. The hGH injection, on the other hand, poses significant risks, both physical and psychological.

These injections are linked in some studies to a potential for increased cancer risk, 5-8 are painful, and may aggravate, rather than reduce, the stigma of short stature. 9,10 Moreover, while growth rate is increased in the short term, it is unclear that the final net height of the child is significantly increased by the treatment.

The Physicians Committee for Responsible Medicine worked to halt these experiments and recommended that the biological and psychological effects of hGH treatment be studied in hormone-deficient children who already receive hGH, and that non-pharmacologic interventions to counteract the stigma of short stature also be investigated. Unfortunately, the hGH studies have continued without modification, putting healthy short children at risk.

Use of Placebo in Clinical Research

Whooping cough, also known as pertussis, is a serious threat to infants, with dangerous and sometimes fatal complications. Vaccination has nearly wiped out pertussis in the U.S. Uncertainties remain, however, over the relative merits and safety of traditional whole-cell vaccines versus newer, acellular versions, prompting the NIH to propose an experiment testing various vaccines on children.

The controversial part of the 1993 experiment was the inclusion of a placebo group of more than 500 infants who get no protection at all, an estimated 5 percent of whom were expected to develop whooping cough, compared to the 1.4 percent estimated risk for the study group as a whole. Because of these risks, this study would not be permissible in the U.S. The NIH, however, insisted on the inclusion of a placebo control and therefore initiated the study in Italy where there are fewer restrictions on human research trials. Originally, Italian health officials recoiled from these studies on ethical as well as practical grounds, but persistent pressure from the NIH ensured that the study was conducted with the placebo group.

The use of double-blind placebo-controlled studies is the “gold standard” in the research community, usually for good reason. However, when a well-accepted treatment is available, the use of a placebo control group is not always acceptable and is sometimes unethical. 11 In such cases, it is often appropriate to conduct research using the standard treatment as an active control. The pertussis experiments on Italian children were an example of dogmatic adherence to a research protocol which trumped ethical concerns.

Placebos, Ethics, and Poorer Nations

The ethical problems that placebo-controlled trials raise are especially complicated in research conducted in economically disadvantaged countries. Recently, attention has been brought to studies conducted in Africa on preventing the transmission of HIV from mothers to newborns. Standard treatment for HIV-infected pregnant women in the U.S. is a costly regimen of AZT. This treatment can save the life of one in seven infants born to women with AIDS. 12 Sadly, the cost of AZT treatment is well beyond the means of most of the world’s population. This troubling situation has motivated studies to find a cost-effective treatment that can confer at least some benefit in poorer countries where the current standard of care is no treatment at all. A variety of these studies is now underway in which a control group of HIV-positive pregnant women receives no antiretroviral treatment.

Such studies would clearly be unethical in the U.S. where AZT treatment is the standard of care for all HIV-positive mothers. Peter Lurie, M.D., M.P.H., and Sidney Wolfe, M.D., in an editorial in the New England Journal of Medicine , hold that such use of placebo controls in research trials in poor nations is unethical as well. They contend that, by using placebo control groups, researchers adopt a double standard leading to “an incentive to use as research subjects those with the least access to health care.” 13 Lurie and Wolfe argue that an active control receiving the standard regimen of AZT can and should be compared with promising alternative therapies (such as a reduced dosage of AZT) to develop an effective, affordable treatment for poor countries.

Control Groups and Nutrition

Similar ethical problems are also emerging in nutrition research. In the past, it was ethical for prevention trials in heart disease or other serious conditions to include a control group which received weak nutritional guidelines or no dietary intervention at all. However, that was before diet and lifestyle changes—particularly those using very low fat, vegetarian diets—were shown to reverse existing heart disease, push adult-onset diabetes into remission, significantly lower blood pressure, and reduce the risk of some forms of cancer. Perhaps in the not-too-distant future, such comparison groups will no longer be permissible.

The Ethical Landscape

Ethical issues in human research generally arise in relation to population groups that are vulnerable to abuse. For example, much of the ethically dubious research conducted in poor countries would not occur were the level of medical care not so limited. Similarly, the cruelty of the Tuskegee experiments clearly reflected racial prejudice. The NIH experiments on short children were motivated to counter a fundamentally social problem, the stigma of short stature, with a profitable pharmacologic solution. The unethical military experiments during the Cold War would have been impossible if GIs had had the right to abort assignments or raise complaints. As we address the ethical issues of human experimentation, we often find ourselves traversing complex ethical terrain. Vigilance is most essential when vulnerable populations are involved.

• Frank C. Conahan of the National Security and International Affairs Division of the General Accounting Office, reporting to the Subcommittee of the House Committee on Government Operations.
• Flieger K. Testing drugs in people. U.S. Food and Drug Administration. September 10, 1997.
• U.S. General Accounting Office. FDA Drug Review: Postapproval Risks 1976-85. U.S. General Accounting Office, Washington, D.C., 1990.
• MedWatch, U.S. Food and Drug Administration. Labeling changes related to drug safety. U.S. Food and Drug Administration Home Page; http://www.fda.gov/medwatch/safety.htm . September 10, 1997.
• Arteaga CL, Osborne CK. Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor. Cancer Res . 1989;49:6237-6241.
• Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen on serum insulin-like growth factor I levels in stage I breast cancer patients. J Natl Cancer Inst . 1990;82:1693-1697.
• Stoll BA. Growth hormone and breast cancer. Clin Oncol . 1992;4:4-5.
• Stoll BA. Does extra height justify a higher risk of breast cancer? Ann Oncol . 1992;3:29-30.
• Kusalic M, Fortin C. Growth hormone treatment in hypopituitary dwarfs: longitudinal psychological effects. Canad Psychiatric Asso J . 1975;20:325-331.
• Grew RS, Stabler B, Williams RW, Underwood LE. Facilitating patient understanding in the treatment of growth delay. Clin Pediatr . 1983;22:685-90.
• For a more extensive discussion of the ethical status of placebo-controlled trials see especially: Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research II: ethical, legal and regulatory myths. J Law Med Ethics . 1996;24:252-259.
• Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunnodeficiency virus in developing countries. N Engl J Med . 1997:337:12:853.

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A Brief History of Human Challenge Trials

For more than two centuries, scientists have been intentionally infecting patients with dangerous diseases in order to learn more

Theresa Machemer

Correspondent

Physicians promise in the Hippocratic oath to keep their patients from harm, so intentionally exposing people to a deadly disease would seem to run counter to that contract. But with human challenge studies, they do exactly that. In challenge studies, medical professionals purposefully expose patients to illnesses so that they can study the patient’s symptoms and immune system response. Such studies can also help physicians discover what vaccines will work to prevent the affliction. Historically in such experiments, the health of individual patients, usually voluntary but at times, horrifically, not, has been sacrificed for medical knowledge and future treatments.

Researchers are planning new human challenge trials as the race to develop vaccines against Covid-19 is in a full sprint, with Pfizer’s vaccine receiving authorization in several countries and Moderna’s not far behind. But the end of the pandemic won’t just come from these two pharmaceutical breakthroughs. In order to fully contain the spread of Covid-19, many treatments and vaccines may be necessary in order to vaccinate billions of people. And some experts say that the fastest way to test those second-generation vaccines is through human challenge trials.

Imperial College London intends to begin a human challenge study related to Covid-19 as soon as January. During the study, scientists would purposely infect up to 100 young, healthy volunteers with the coronavirus that causes Covid-19 in the hopes of accelerating the search for new vaccines.

Supporters of the controversial Covid-19 human challenge trial argue that if it can be done safely then it provides a uniquely controlled environment to study factors that are difficult to unravel in longer, large-scale Phase III trials of thousands of people. Critics say that challenge studies are either unnecessary because of vaccine successes so far, or should be put on pause until a later date when they can be run safely. Critics also point out that safety is a concern even for young volunteers because scientists do not know how to treat Covid-19 or what its long-term effects are, and evidence presented by the World Health Organization in September showed that at least a fifth of people between 18 and 34 who catch Covid-19 experience prolonged symptoms.

The debate over such a contentious experiment is nothing new. Human challenge trials are as old as inoculation itself. In 1796, English surgeon Edward Jenner tested the world’s first vaccine by exposing his gardener’s 8-year-old son to cowpox and then smallpox. Human challenge trials have since been used to study dozens of diseases from cholera to cancer, but early studies often put participants directly in harm’s way, not always with their knowledge.

Today, challenge studies undergo careful review by boards of experts before they can begin. A key requirement of an ethical study is that volunteers provide informed consent , proving that they understand the risks of joining a study. The first informed consent process was introduced more than a century after Jenner’s human challenge study.

In 1898, as the U.S. warred with Spain in Cuba, yellow fever —which can cause liver damage, nausea, high fever and bleeding—killed 13 times more soldiers than war wounds. So in 1900, the U.S. Army established a commission led by pathologist Walter Reed to figure out how yellow fever spread and how to stop it. Because only humans seemed to fall ill with the disease, Reed and three colleagues on the commission designed a human challenge study to test a leading theory of yellow fever transmission: mosquito bites.

Reed recognized that if he was correct, then the study itself would be incredibly risky. The need to expose volunteers to deadly disease would have to be weighed with the responsibility to keep the volunteers safe.

“The general that created the commission told Walter Reed… that he had to be absolutely sure that no harm would be caused to the volunteers,” says Enrique Chaves-Carballo , a historian of medicine at the University of Kansas. “He was pretty specific about that.”

To balance his superior’s order with the study’s inherent risk, the commission came up with a novel solution: the first informed consent contract. The commission created a document for volunteers to sign, stating that they understood the study’s risks. However, the form suggested that abstaining from the study was risky, too. The contract stated :

“The undersigned understands perfectly well that in the case of the development of yellow fever in him, that he endangers his life to a certain extent but it being entirely impossible for him to avoid the infection during his stay in the island, he prefers to take the chance of contracting it intentionally in the belief that he will receive from the said Commission the greatest care and the most skillful medical service.”

During the experiment, the scientists first allowed mosquitoes to bite yellow fever patients so the insects would pick up the disease. Then, they brought the mosquitoes to healthy volunteers, and allowed the mosquitoes to bite them. When volunteers fell ill, Reed scoured blood samples for the microbe causing their illness.

Those with yellow fever were prescribed complete bed rest and fasting except for “a few sips of champagne” and some pain medication, says Chaves-Carballo. Volunteers received a hefty payment of $100 in gold per mosquito bite, and another $100 if they fell ill.

In the first round of experiments, 11 volunteers got mosquito bites. Two fell ill, and survived. The third man to fall ill, Jesse W. Lazear, was one of the scientists running the study. He was bitten by accident and died of yellow fever 12 days later.

Though Reed considered ending the study after the death of his colleague, the commission instead named a sanitary station Camp Lazear in his honor. And by 1901 , Reed and the commission had shown through their mosquito bite experiments that the insects transmit yellow fever. Inoculation of more volunteers with yellow fever patients’ filtered blood samples showed that a virus causes the disease—making yellow fever the first human virus scientists discovered.

With the disease-causing culprit identified, Reed returned to George Washington University (then Columbian University) to teach, and other scientists picked up the search for a yellow fever vaccine. U.S. army physician William Gorgas and Cuban-born physician Juan Guiteras established an inoculation station for a new round of human challenge studies in Havana. They hoped to learn how to induce light cases of yellow fever with mosquito bites in order to give people immunity. More than 20 volunteers signed up for the first experimental inoculations in 1901, including the only woman to participate in the study, a military nurse named Clara Maass.

Maass was bitten five times without developing yellow fever, and received $100 to send home to her mother and nine siblings in New Jersey—a huge sum compared to her monthly pay of $30 .

Her sixth mosquito bite proved fatal. She and two other volunteers were infected with a particularly violent strain of the virus—the doctors didn’t know how to induce just light cases—and all three died in August of 1901.

“Some of the headlines of the newspapers are like, ‘Nurse Dies for a Hundred Dollars,’” says Chaves-Carballo. “People responded to the fact that she was a young nurse who was trying her best to help her family.”

Public outcry in the U.S. brought the Havana experiments to an end. Maass’ death brought the study’s exorbitant pay under fire, as such a large incentive may have interfered with the participants’ ability to accurately weigh the risk of joining the study. The fact that the study was run by the U.S. Army, and Reed’s participants were members of the military, also brought into question the participants’ ability to freely opt out of the study, says Monica McArthur , pediatrician and infectious disease specialist at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health.

“In a lot of the studies early on, the Walter Reed experiment and other studies, used what we would now consider vulnerable populations,” people who couldn’t freely agree to participate or make a fully informed decision, says McArthur. “Prisoners, for example, could be enrolled in studies.”

A classic example of a challenge study that relied on a vulnerable population is the Tuskegee Syphilis Study. Beginning in 1932 , the U.S. Public Health Service recruited about 600 poor African American men from around Tuskegee, Alabama, for a study of how syphilis worsens over time. About two-thirds of the men had syphilis, but the study doctors informed them they had “bad blood.”

After receiving this phony diagnosis, the men were persuaded to join the study in exchange for free meals, hospital access and treatment for “bad blood” and other unrelated conditions. The scientists also provided participants a burial stipend that would be paid to their survivors after their deaths.

Only about half of the men with syphilis received a treatment that was usually prescribed in the 1930s: doses of toxic arsenic and mercury. The doctors subjected the participants to blood draws and spinal taps, and after they died of syphilis, autopsies, all in pursuit of more information about the natural course of the disease. The study lasted for decades, and even after the medical community established that penicillin could cure the disease in the 1940s the men did not receive the medication.

In 1972, journalist Jean Heller of the Associated Press brought the Tuskegee Syphilis Study to light and shared how the doctors involved in the study had deceived the men participating. By then, only 74 of the men with syphilis still survived. Public outrage shut the study down three months after the report.

While the Tuskegee Syphilis Study relied on participants who were already ill, other studies exposed otherwise healthy people to deadly diseases. For example, from 1955 to 1970, a pediatrician exposed more than 50 children with mental disabilities to hepatitis in order to identify different strains of the disease and eventually develop vaccines. The trial took place at Willowbrook State School, a home for children and adults with developmental disabilities in Staten Island, New York.

The school was overcrowded and had a lengthy waitlist for new patients. But the study’s principal investigator, Saul Krugman, offered several parents the opportunity to cut the line if they agreed to enroll their children in the study. Krugman told them that their children were likely to catch the disease at the facility anyway, but by joining the study, they would have access to cleaner facilities and a chance at an eventual vaccine.

“I did feel coerced,” said Diana McCourt, who enrolled her daughter in the Willowbrook study, to Forbes ’ Leah Rosenbaum. “I felt like I was denied help unless I took this [opportunity].”

The Willowbrook studies, which ended in 1970, revealed the existence of the A and B strains of hepatitis and sped up the development of a hepatitis B vaccine. But the studies progressed even as some in the medical community criticized Krugman’s methods. In 1966, anesthesiologist Henry K. Beecher published a landmark essay detailing 22 examples of ongoing unethical research on human subjects, including the Willowbrook hepatitis studies, in order to raise awareness and end unethical practices that continued despite the creation of international human experimentation guidelines—the Nuremberg Code in 1947 and the Declaration of Helsinki in 1964.

In addition to the Willowbrook study, Beecher highlighted one study in which melanoma, a serious form of skin cancer, was transferred from a woman to her mother “in the hope of gaining a little better understanding of cancer immunity.” The woman died on the same day that her mother was to receive the melanoma injection, so the doctors knew the cancer was deadly. Her mother died 451 days after receiving the injection.

Beecher concluded that an ethical approach to experimentation requires, first and foremost, the informed consent of study volunteers. “The difficulty of obtaining this is discussed in detail,” he writes, “But it is absolutely essential to strive for it for moral, sociologic and legal reasons. The statement that consent has been obtained has little meaning unless the subject or his guardian is capable of understanding what is to be undertaken and unless all hazards are made clear.”

Human challenge studies became less common after the 1970s with the conclusion of unethical studies that shocked the public. Since then, the Declaration of Helsinki has been amended seven times to clarify ethical standards for human experiments, most recently in October of 2013. The current declaration states that “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.”

When run well, challenge studies are still uniquely able to provide clear data about infectious diseases. “They are now coming back in favor with very rigorous ethical principles in place,” adds McArthur.

The University of Maryland used human challenge studies in 2012 and 2013 to develop a vaccine for cholera , which was approved by the FDA in 2016. Cholera was an ideal candidate for a safe human challenge study because it is well understood by scientists, is reliably treatable with fluids and antibiotics, and has no long-term effects after the infection is gone.

Informed consent procedures have come a long way since Reed’s contract. Volunteers can ask questions and seek outside guidance, and must pass an assessment designed by the researchers to prove that they understand the risks of a study. And the volunteers have the power to quit. “Every time there’s an encounter with the volunteer, it’s reaffirming that the volunteer is still willing and able to participate,” says McArthur.

According to a statement by Imperial College London, which still needs to have its experimental plan approved by government regulators before researchers can begin recruiting participants, volunteers’ safety is the number one priority. “It would be nice to see exactly how [Imperial College London] explains the risks and benefits to those participating in this study,” says Chaves-Carballo.

Covid-19 is different from other challenge study diseases: Scientists have been studying it for less than a year, physicians have no approved treatments to intervene if a volunteer’s illness becomes severe, and early evidence suggests Covid-19 can cause long-term effects even in young, previously healthy people. The Imperial College London study aims to first identify the minimum dose of coronavirus necessary to cause disease. The study would use that dose of virus to study how vaccines work in the body to prevent Covid-19, to look at potential treatments and study the immune response. The biomedical community remains split on whether such a study should be run, given all of the unknowns around Covid-19.

When scientists develop second- and third-generation vaccines, a challenge study allows researchers to work with just 100 people instead of tens of thousands. That means fewer people are asked to go without the vaccine for the sake of research. And by waiting to conduct a challenge study on Covid-19 until a later date, researchers might get access to new information about risk factors for severe disease, which could help make the study safer.

“I am not a fan of SARS-CoV-2 challenge studies,” says McArthur. “But if I’m playing devil’s advocate against myself, some of the very reasons [not to do a challenge study] that I listed might be reasons that someone else might say that a challenge study is beneficial. Because we don’t know that much about a disease, so we could learn more about it.”

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Theresa Machemer is a freelance writer based in Washington DC. Her work has also appeared in National Geographic and SciShow. Website: tkmach.com

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While Some Unethical, These 4 Social Experiments Helped Explain Human Behavior

How have we learned about human behavior some studies caused a baby to fear animals — and other experiments helped us explore human nature..

From the CIA’s secret mind control program, MK Ultra, to the stuttering “Monster” study, American researchers have a long history of engaging in human experiments. The studies have helped us better understand ourselves and why we do certain things.

These four experiments did just this and helped us better understand human behavior. However, some of them would be considered unethical today due to either lack of informed consent or the mental and/or emotional damage they caused.

1. Cognitive Dissonance Experiment

After proposing the concept of cognitive dissonance , psychologist Leon Festinger created an experiment to test his theory that was also known as the boring experiment. 

Participants were paid either $1 or $20 to engage in mundane tasks, including turning pegs on a board and moving spools on and off a tray. Despite the boring nature of the activities, they were asked to tell the next participant that it was interesting and fun.

The people who were paid $20 felt more justified lying to others because they were better compensated — and they experienced less cognitive dissonance . Participants who were paid $1 felt greater cognitive dissonance due to their inability to rationalize lying.

In an attempt to reconcile their dissonance, they convinced themselves that the tasks were actually enjoyable.

2. The Little Albert Experiment  

In 1920, psychologist John. B. Watson and graduate student (and future wife) Rosalie Rayner wanted to see if they could produce a response in humans using classical conditioning — the way Pavlov did with dogs.  

They decided to expose a 9-month-old baby, whom they called Albert, to a white rat. At first, the baby displayed no fear and played with the rat. To startle Albert, Watson and Rayner would then make a loud noise by hitting a steel bar with a hammer. 

Each time they made the loud sound while Albert was playing with the rat, he became frightened, started crying, and crawled away from the rat. He had become classically conditioned to fear the rat because he associated it with something negative. He then developed stimulus generalization, where he feared other furry white objects — including a rabbit, white coat, and a Santa mask. 

3. Stanford Prison Experiment

In 1971, Stanford psychologist Philip Zimbardo designed a study to examine societal roles and situational power — through an experiment that recreated prison conditions. 

Zimbardo created a mock prison in a building on Stanford’s campus. He assigned study participants to be either guards or prisoners. Prisoners were given numbers instead of names, had a chain attached to one leg, and were dressed in smocks and stocking caps.

Those assigned to the role of a guard quickly conformed to their new position of power. They became hostile and aggressive toward the prisoners, subjecting them to psychological and verbal abuse — despite never having previously demonstrated such attitudes or behavior. The experiment was slated to last two weeks but needed to be ended after only six days. 

4. The Facial Expression Experiment

In 1924, psychology graduate student Carney Landis wanted to study how people’s emotions were reflected in their facial expressions, exploring whether certain emotions caused the same facial expressions in everyone.

Landis marked participants’ faces with black lines to study the movement of their facial muscles as they reacted. At first, he had them do innocuous tasks, such as listening to jazz music or smelling ammonia. 

As Landis grew frustrated that their responses weren’t strong enough, he had participants engage in increasingly shocking acts, such as sticking their hands into a bucket with live frogs in it. Eventually, Landis instructed participants to decapitate a live mouse. If they refused, he decapitated the mouse himself to elicit a strong reaction from them.

Read More: 5 Unethical Medical Experiments Brought Out of the Shadows of History

Article Sources

Our writers at Discovermagazine.com use peer-reviewed studies and high-quality sources for our articles, and our editors review for scientific accuracy and editorial standards. Review the sources used below for this article:

Advance Research Journal of Social Science . Cognitive dissonance: its role in decision making

New Scientist. How a baby was trained to fear

Stanford Prison Experiment. Philip G. Zimbardo

Incarceration . The dirty work of the Stanford Prison Experiment: Re-reading the dramaturgy of coercion

Journal of Experimental Psychology. Studies of emotional reactions. I. 'A preliminary study of facial expression."

The American Journal of Psychology. Carney Landis: 1897-1962

Allison Futterman is a Charlotte, N.C.-based writer whose science, history, and medical/health writing has appeared on a variety of platforms and in regional and national publications. These include Charlotte, People, Our State, and Philanthropy magazines, among others. She has a BA in communications and a MS in criminal justice.

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A Controversial Rewrite For Rules To Protect Humans In Experiments

Throughout history, atrocities have been committed in the name of medical research.

Nazi doctors experimented on concentration camp prisoners. American doctors let poor black men with syphilis go untreated in the Tuskegee study . The list goes on.

To protect people participating in medical research, the federal government decades ago put in place strict rules on the conduct of human experiments.

Now the Department of Health and Human Services is proposing a major revision of these regulations, known collectively as the Common Rule . It's the first change proposed in nearly a quarter-century.

"We're in a very, very different world than when these regulations were first written," says Dr. Jerry Menikoff , who heads the HHS Office of Human Research Protections. "The goal is to modernize the rules to make sure terrible things don't happen."

Many of the revisions are long overdue and would significantly improve oversight of scientific research, say researchers, bioethicists and officials who oversee human research studies.

But many of the updates are also triggering intense debate and criticism.

The new rules are too complex and too vaguely written in many places, says Elisa Hurley , executive director of Public Responsibility in Medicine and Research, a nonprofit organization in Boston. As such, she says, they could cause confusion for volunteers and researchers. It's a "flawed attempt" to improve things, Hurley says.

After hearing such criticism and receiving numerous requests to give the public more time to study the proposed revisions, the HHS office announced Tuesday that it was extending the public comment period by 30 days — to Jan. 6.

One change that some object to would require scientists to obtain explicit consent from patients before using their blood or tissue for research. The requirement aims to prevent a repeat of what happened to Henrietta Lacks . She was an African-American woman who died of cervical cancer in 1951. Cells taken from her cervix were used without her consent to produce a research cell line that has been kept alive in labs around the world ever since.

A color-enhanced scanning electron micrograph shows HeLa cells, which are commonly used in biomedical experiments. The research cell line was derived from cervical cancer cells taken from Henrietta Lacks in 1951. Science Source hide caption

A color-enhanced scanning electron micrograph shows HeLa cells, which are commonly used in biomedical experiments. The research cell line was derived from cervical cancer cells taken from Henrietta Lacks in 1951.

Researchers and companies use these cells in a wide range of research, including the development of new drugs. Neither Lacks nor her family consented to this use.

Under the new rules, scientists would only be able to do research on biological specimens from people who explicitly agree to it: " 'I'm OK with that. I'm OK with future research studies taking place using the leftover portions of my tumor or blood,' " Menikoff says.

But some scientists argue that in most cases the new requirement would create unnecessary red tape that would significantly impede important research.

"It's now going to be much more onerous to get this tissue that otherwise would just go in the trash," says Dr. Luis Garza , a Johns Hopkins University dermatologist who uses foreskin from circumcisions for a variety of experiments. "It's creating barriers for working on human tissue, which is what we need to do to solve human disease."

Another revision would expand the number of studies that would have to follow the rules. All scientists who get federal funding would be required to adhere to the rules for every experiment they conduct, even those that aren't funded directly by the government.

Other changes are designed to make some research easier, such as conducting large studies involving multiple institutions. Right now, independent panels known as institutional review boards, or IRBs, oversee studies in each location where people volunteer. Under the proposed rules, one centralized IRB could run an entire multicenter study.

"It is all one study," HHS' Menikoff says. "So basically the same ethical rules apply to all of the subjects in the study."

He says the issues raised by any given study are pretty much the same at one study site compared to another site, so that duplicate ethical reviews can be eliminated. He and other researchers say the proposed change would help get new cures to patients more quickly.

But some advocates and bioethicists worry that streamlining study reviews in this way would undermine protections for volunteers, especially studies involving many sites, says Dr. Michael Carome , who heads Public Citizen's Health Research Group, a Washington, D.C.-based advocacy group.

It's unlikely one IRB can "adequately understand the local context, local ethical issues, the quality of the facilities and the credentials of the practitioners," he says. "That one IRB is unlikely to have sufficient knowledge of all those sites."

The proposal would also exempt many studies that don't pose physical risks. Examples include projects that only involve asking subjects questions and answers — things like surveys and in-depth interviews. The idea is to get rid of unnecessary bureaucratic hoops for harmless research, Menikoff says.

But this change is raising fears, too.

"I think that's a major step backwards that, as far as I'm concerned, takes us back into the dark ages," says Ruth Macklin , a bioethicist at the Albert Einstein College of Medicine in New York.

Those kinds of studies "are not physically invasive, but they may be intrusive," Macklin says. "There are forms of harm that are not just physical harm."

Probing people about sensitive subjects, such as whether they've had an abortion or have been physically or sexually abused as children, can trigger strong emotional reactions, potentially causing psychological distress, Macklin says.

Menikoff disputes whether the changes would put anyone at risk. But he says the government will consider all the feedback it gets before changing the rules.

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Why Human Subjects Research Protection Is Important

Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study. The road leading to the current regulations and ethical considerations has been long and checkered.

Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations.

Results: Key documents—from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011—that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research.

Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research. The examples also reinforce the importance of individual responsibility. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities.

INTRODUCTION

Participation of human subjects in research presents a challenging ethical dilemma. A research subject may be asked to participate in a study of no benefit and no substantial risk or in a study with the potential for significant benefit but also significant risk. In placebo-controlled studies, subjects may be exposed to significant risk for no benefit to the individual. These variants are confounded by treatment protocols—most commonly encountered in oncology trials—that compare the effect of an investigational arm to the standard of care, further blurring the distinction between research and medical treatment.

Institutional review boards (IRBs) have the federally mandated responsibility to review research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in the study. The road leading to the current regulations and ethical considerations has been long and checkered. The system that has evolved minimizes the risks for unethical behavior and serious adverse events but is not infallible. Understanding how we have arrived at the current approach and analyzing some of the ethical lapses that directed this course support efforts to continually reevaluate the regulations in order to improve the safety of subjects who are willing to participate in research activities.

EVOLUTION OF HUMAN SUBJECTS PROTECTION

Our current approach to human subjects protection has evolved with efforts to understand questionable ethical behavior in research over the course of several hundred years. One might suggest that the jester conscripted to sample the king's food to ensure that it was safe to eat presaged the use of vulnerable populations as subjects for research, but the evolution of the management of smallpox is perhaps a more applicable early perspective on research in humans. Three centuries ago, reports of good outcomes following variolation—inhalation of the scabs from persons infected with smallpox—were circulating in Asia. In 1717, Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey, became an advocate of variolation after learning about it in Constantinople. In 1721, after she returned to England, Lady Montagu and the Princess of Wales urged variolation of “several prisoners and abandoned children” by having smallpox scabs inserted under their skin. Several months later, the children and prisoners were deliberately exposed to smallpox. When none contracted the disease, the procedure was deemed safe, and members of the royal family were treated according to this new protocol. 1

Later that same century, Edward Jenner developed inoculation with a vaccine. Many of his contemporaries had noted that milkmaids who had contracted cowpox seemed immune to the much more lethal smallpox. In May 1796, Jenner isolated material from the cowpox lesions on the milkmaid Sarah Nelms and inoculated 8-year-old James Phipps who developed fever and malaise about 9 days after the inoculation. Some accounts report that Phipps was the son of Jenner's gardener. A few months later, Jenner deliberately inoculated Phipps with material from fresh smallpox lesions, and the child remained healthy. The adoption of this process was not immediate but slowly spread and is widely cited as the first scientific approach proving vaccination. 2

This early use of children and prisoners portends a long history of selecting what are now considered vulnerable populations to be the subjects of research. Participation was commonly without consent, with no knowledge of their participation, and with no explanation of the research. Information was withheld from those selected to participate in research activities perceived as dangerous to more acceptable members of society, and the therapies developed were generalized only if they were proven relatively safe and effective in what are now recognized as vulnerable populations.

Numerous instances of research experiments in subsequent years exposed vulnerable subjects to risk, including a pivotal research disaster in Germany just before World War II that led to regulations for human subjects participation in research projects.

The Reich Circular of 1931

As reported by Sir Graham Wilson in the book The Hazards of Immunization , “Between 10 December 1929 and 30 April 1930, 251 of 412 infants born in the old Hanseatic town of Lubeck received three doses of BCG [bacillus Calmette-Guerin] vaccine by the mouth during the first ten days of life. Of these 251, 72 died of tuberculosis, most of them in two to five months and all but one before the end of the first year. In addition, 135 suffered from clinical tuberculosis but eventually recovered; and 44 became tuberculin-positive but remained well.” 3

Bonah and Menut describe how Albert Calmette was able to establish the BCG vaccine as a nonexperimental “prophylactic treatment” against tuberculosis. 4 By definition, a medical experiment, as opposed to any other medical action, has definite ethical implications and consequences. Even though the BCG vaccine was in experimental stages, Calmette convinced a court that the vaccine was a “post-experimental, routine medical treatment.” By avoiding the definition of an experiment, Calmette did not have to inform the children's parents about the risks of the vaccine. As a result of this tragedy, Dr Julius Moses, a critic of unethical human experimentation who referred to “experimental mania,” drafted guidelines for human experimentation. After debate in parliament and the press, the guidelines were published and became official in 1931. The guidelines applied to everyone in Germany. 5 , 6

These rules for research in human subjects were issued as the Reich Circular of 1931 ( Figure 1 ). The document is quite informative for its contrast with later events in Germany and worth reviewing for correlation with ethical concepts now well accepted in ethical thinking. It is worth noting that these guidelines emphasize special responsibilities for utilization of “innovative therapy,” suggesting a similar level of responsibility for these procedures as for research.

The Reich Circular, 1931 6

World War II and the Nuremberg Code

Despite the ethical ideals espoused in the Reich Circular, the travesty of the Holocaust followed shortly afterward, leading to war criminal trials after the surrender of Germany ended World War II in Europe.

The Nuremberg trials that began in 1945 and concluded in 1947 were held in response to the atrocities Germany committed during the war. The so-called Doctors’ Trial represents a major turning point in human research protection. Twenty-three physicians were indicted, accused of crimes against humanity by conducting criminal scientific and medical experiments on concentration camp prisoners. Sixteen defendants were found guilty. 7

Several German doctors had argued that no international law or informal statement differentiated between legal and illegal human experimentation, despite the aforementioned Reich Circular. Two US doctors who worked with the prosecution during the trial, Andrew Ivy and Leo Alexander, objected to this argument. On April 17, 1947, Dr Alexander submitted a memorandum to the United States Counsel for War Crimes outlining 6 points defining legitimate medical research. The trial verdict reiterated almost all of these points in a section entitled Permissible Medical Experiments and expanded the original 6 points into 10. These 10 points became known as the Nuremberg Code ( Figure 2 ). 8

The Nuremberg Code, 1947 10

Similar atrocities were carried out on Chinese citizens in Japanese camps; of particular note are the biological warfare experiments at Unit 731 in the Pacific theater that were obscured by agreements made during the surrender of Japan and with the complicity of the United States. 9 The details of these atrocities remained classified until they were acknowledged by Congress in the Japanese Imperial Government Disclosure Act of 2000 (Pub L No. 106-567, Title VIII of the Intelligence Authorization Act of 2000) that called for declassification and release of records related to Japanese war crimes during World War II. 10

Declaration of Helsinki

The tenets of the Nuremberg Code, while guiding the future for human research protection, represent a military code of conduct with no standing in civil international or US law. By absolutely requiring the voluntary consent of the individual, the Nuremberg Code notably does not address the needs of children or other special populations unable to provide consent. The Nuremberg Code inspired the World Medical Association (WMA)—an international association currently comprised of 114 national medical associations, including the American Medical Association—to propose a similar code of conduct for participating members by publishing the Declaration of Helsinki in 1964. This document reiterates the provisions of the Nuremberg Code and expands the provisions to allow for the participation of children and other potentially compromised subjects in research. The Declaration of Helsinki serves as a guideline for ethical research and has been amended 7 times, most recently at the WMA General Assembly in October 2013, to reflect contemporary ethical issues as they have evolved since the initial statement in 1964. 11

Ethics Violations in the United States

Meanwhile, research continued in the United States with particular concerns attached to research involving vulnerable populations, exemplified by numerous studies involving institutionalized children and studies that breached ethically sound research practices. Henry Beecher, a well-recognized physician at Massachusetts General Hospital, surveyed the contemporary literature to identify ethical concerns and organized lectures around his observations. These lectures eventually culminated in a special article published in the New England Journal of Medicine in 1966. 12

In “Ethics and Clinical Research,” Beecher reported that he had reviewed 100 consecutive articles published in 1964 “in an excellent journal,” and after culling his list to address the editor's request, selected 12 articles that demonstrated serious ethical concerns. The purpose of Beecher's article was to demonstrate the widespread lapse in ethical issues in medical research and to encourage reform in the ethical approach to human subjects research that inspired Congress to reconsider legislative reforms for human subjects protection.

An article by Jean Heller that appeared in the Washington Star on July 25, 1972 placed an exclamation point in the history of human research ethics. 13 Heller reported on a long-term study sponsored by the US Public Health Service on the effect of syphilis if left untreated in poor rural African American subjects. Officially known as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” the study enrolled 399 subjects with syphilis and 201 uninfected controls from the African American community surrounding Tuskegee, AL for “treatment of bad blood.” In exchange for taking part in the study, the men received free medical examinations, free meals, and burial insurance but were not given the benefit of providing informed consent. No treatment was provided; the research plan was to follow the subjects to establish a natural history for the disease if left untreated. Although originally projected to last 6 months, the study continued for 40 years. 14

Treatments available at the onset of the trial in 1932, even if provided, were not very effective and would have been heavy metals, involving at least 30 months of treatment, a 30% cure rate, and significant toxicity. By 1945, penicillin had been proven to be an effective therapy for syphilis with few side effects. Once penicillin was established as effective, the US Public Health Service set up centers for treatment but determined that the data from the Tuskegee experiments were too important to abandon and decided that the study should be continued with no treatment provided to the participants. Similar determinations were made in subsequent years, with the last review occurring as recently as 1969. 14

While medical research such as the Tuskegee study garnered most of the attention for ethical lapses, other areas of research involving human subjects also raised concerns. The Milgram experiments carried out in the early 1960s at Yale University are a lightning rod for discussion of ethical issues in human subjects research in social sciences. 15 Intrigued by the Nuremberg trials defendants’ argument that they were simply following orders, Stanley Milgram set out to determine if the German defendants were particularly obedient to authority figures compared to other members of society. Milgram recruited subjects for an experiment in learning via newspaper ads. The male research subjects were assigned to act as a teacher asking questions of a learner (a confederate of Milgram) who was attached to electrodes. The teachers were instructed to increase the severity of electrical shocks if the learner answered the questions incorrectly. Shocks were labeled from 15v to 450v, with 15v indicated as mild, 300v as severe, and 450v as XXX. Many of the teacher subjects eventually shocked the learner at 450v and exhibited increasing signs of distress as the shocks they delivered increased in perceived severity. 15 These experiments evoked significant concern among those in social sciences in regard to the questionable ethics of the deception used, as well as the potential for long-term psychological harm that might be incurred by unwitting participants.

Federal Policy for Protection of Human Subjects and the National Research Act

The public outcry over the Tuskegee study, other reports of ethical lapses in both medical and social research, and the alarm in the medical community raised by Dr Beecher's article in the New England Journal of Medicine led Congress to action. On May 30, 1974, the US Department of Health, Education, and Welfare (DHEW), responsible for oversight of the National Institutes of Health, replaced previous policies with comprehensive regulations governing the protection of human subjects (45 CFR §46). 16 One month later in July 1974, Congress passed the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 Title II of the act, Protection of Human Subjects of Biomedical and Behavioral Research, created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. Along with being assigned several other tasks, the National Commission was directed to make recommendations to the DHEW secretary about the ethical principles that should underlie human subjects research. 18

The Belmont Report

The National Commission issued several reports in response to the directives. The most notable among a collection of important documents is the Belmont Report, named after the Smithsonian conference center where the group convened, that was issued in 1978. 19 This document, widely regarded as the landmark analysis of ethics in human subjects research, serves as the foundation for discussion of ethical concerns in research ethics involving human subjects, as well as the source of federal regulations for research established by the Office for Human Research Protections (OHRP).

The Belmont Report is divided into three sections. The first section briefly states the National Commission's recognition that even as the report was being written, the distinction between medical practice and research was blurred. The report defines medical practice as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation for success. Research, on the other hand, is defined as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).” This section further expounds on the conflation between the use of the terms experimental and research. When used in reference to a procedure or treatment that significantly deviates from typical (ie, a treatment that is “new, different or untested”), the report notes that an “experimental” treatment is not necessarily research. Although they excluded “experimental” treatment from research and the applicable anticipated regulations, the National Commission strongly recommended that such treatments should eventually be incorporated into formal research protocols “to determine if they are safe and effective.” The first section of the Belmont Report concludes with the recognition that practice and research may go hand in hand: “the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.” 19 This language is reminiscent of the Reich Circular recommendation regarding “innovative therapy.”

The second section is the heart of the report and defines three principles that should guide the discourse surrounding any ethical concerns related to research in human subjects: respect for persons, beneficence, and justice. The principle of nonmaleficence, now commonly accepted as one of the four principles of biomedical ethics, was notably absent.

• Respect for persons : The principle of respect for persons requires that “individuals should be treated as autonomous agents,” and those with “diminished autonomy are entitled to protection.” These concepts inform “two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.” The National Commission defines the elements that would be necessary to qualify as an autonomous individual and explores circumstances that would define those who should be considered to be of diminished autonomy and thus deserving of protection.
• Beneficence : The principle of beneficence as defined by the National Commission encompasses the concept of do no harm included in the Hippocratic Oath and notes that the term is commonly thought “to cover acts of kindness or charity that go beyond strict obligation.” The National Commission proposes two general rules that inform beneficence as an obligation: “(1) do not harm and (2) maximize possible benefits and minimize possible harms.” The implications of these duties within the context of both individual investigators and society at large are examined.
• Justice : The principle of justice is posed as the following question: “Who ought to receive the benefits of research and bear its burdens?” This principle is broad in potential implications and can be summarized as evaluating the appropriate distribution of the risks and burdens of research among individuals, groups, or even situations in which inherent inequalities may need to be considered to reach an ethically informed decision. The National Commission proposes the following framework for beginning these discussions: “(1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.” The discussion of justice continues with the historic context for including the principle of justice and how lapses in justice (ie, the Tuskegee study) were the primary impetus for the formation of the National Commission.

The final section of the Belmont Report addresses the application of these principles and the implications of their requirements when considering three important elements of research involving human subjects: informed consent, assessment of risks and benefits, and selection of subjects for research.

Informed consent. The consent process has three components: information, comprehension, and voluntariness. Reaching agreement on an appropriate standard for evaluating the quality of information that should be provided to potential participants about a proposed research project is difficult and eventually ends with the suggestion that the standard of “the reasonable volunteer” might best fulfill the requirements of respect for persons, beneficence, and justice. A caveat is provided, citing the problem posed by research where “informing subjects of some pertinent aspect of the research is likely to impair the validity of the research,” a key area of ethical concern (lack of disclosure) raised by the Milgram study discussed previously. The National Commission proposes that such studies may only be appropriate if “(1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them,” further noting that “Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.” 19

Regarding the component of comprehension, the Belmont Report states, “The manner and context in which information is conveyed is as important as the information itself.” The level of comprehension is also important within the context of the individual's ability to understand the information, with emphasis that the obligation for ensuring subject understanding increases in importance relative to the level of risk posed by participation in the study. The National Commission suggests that some level of questioning the subject to ensure comprehension is appropriate and even suggests that written responses to questions may be appropriate if risks are exceptionally high. 19 If participation of subjects with compromised abilities is anticipated, researchers must be particularly diligent in evaluating the level of comprehension by the subject's proxy and ensure that the proxy is indeed capable of representing the best interests of the subject. The report even suggests that the proxy might need to be present or available during the research interventions to withdraw the subject from the study if the proxy perceives that withdrawal may be in the subject's best interest.

Voluntariness is a concept consistently emphasized in the Reich Circular, the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. Although voluntariness may appear to be self-evident, it may be the most difficult concept to address. The Belmont Report emphasizes that the subject must be “free of coercion and undue influence.” Coercion is specifically defined as “an overt threat of harm” and in most circumstances is relatively easy to evaluate. However, arguments can be made about what defines “undue influence.” Discussions about appropriate levels of compensation for participation are common, particularly when studies involve financial or other considerations made to possibly financially compromised subjects. The Belmont Report specifically notes, “inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.” Other concerns related to undue influence involve social standing, employment, or other circumstances that may be difficult to assess but are worthy of consideration for individual subjects.

Assessment of risks and benefits. The National Commission notes that a favorable risk/benefit assessment is associated with the principle of beneficence. This definition is particularly appropriate in that the National Commission's interpretation of beneficence includes the duty of nonmaleficence. The Belmont Report examines the meaning of risk and benefit in the setting of potential types of harm that may be experienced by individual subjects, the families of the individual subjects, society at large, or special groups of subjects in society. Benefits are also discussed in relation to the individual and society at large. In summarizing the risks and benefits of research, the Belmont Report states

…assessment of the justifiability of research should reflect at least the following considerations:

Brutal or inhumane treatment of human subjects is never morally justified.

Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures.

When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject—or, in some rare cases, to the manifest voluntariness of the participation).

When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits.

Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. 19

Selection of subjects for research. The third element, selection of subjects for research, finds its primary guidance in the principle of justice where the moral requirements demand that the procedures and outcomes for the selection of subjects are fair to the individual and within the social context. Participation in potentially beneficial research should be fairly distributed to all who wish to participate, and risky research should not be offered only to less desirable subjects. In the context of society, risks should be distributed after careful consideration of the burdens and the ability of individuals in identifiable groups to bear those burdens. As a generalization, adults should be considered before children, and participation by institutionalized individuals should invoke very careful consideration. Even with these safeguards, the National Commission believed that the selection of subjects may continue to reflect injustice arising from social, racial, sexual, and cultural biases institutionalized in society. Harking back to the ethical concerns that prompted the National Commission, the Belmont Report concludes with the following: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.” 19

Although not included in the body of the report, a footnote specifically addresses the difficulty in extrapolating these tenets to human subjects research in the social sciences: “Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.” 19 An appropriate ethical approach for some areas of social and psychological studies remains elusive. Matthew Salganik, professor of sociology at Princeton University, discusses the issues surrounding the difficulty in applying the Belmont Report recommendations at his blog. 20

The Belmont Report was submitted to Congress on April 18, 1979.

Other Reports by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research

Although the Belmont Report is the centerpiece for the analysis of research in human subjects, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research provided significant additional guidance for Congress to consider as the legislators moved forward to formulate regulations for the governance of human subjects in research. During the 4 years of the National Commission's appointment, other publications provided analysis of concerns related to specific questions (Table), and many of the recommendations were incorporated into the subsequent regulations for human subjects protection. 21

Table .

Human Subjects Protection in Research Reports From the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1974-1978 21

FOIA, Freedom of Information Act.

Principles of Biomedical Ethics

Another landmark publication from 1979 deserves attention for its sustained influence on the field of biomedical ethics and its deviation from the three ethical principles put forth by the Belmont Report. In Principles of Biomedical Ethics , Tom Beauchamp and James Childress argue for inclusion of nonmaleficence as an independent principle to formulate the now-familiar four principles that inform contemporary bioethical discourse. 22 As previously noted, nonmaleficence is considered a duty under the umbrella of the principle of beneficence in the Belmont Report. Beauchamp and Childress maintained that the tradition to do no harm central to the tenets of the Hippocratic Oath incorporates the concept of nonmaleficence at its core and is essential to any discussion of the ethics of medical practice. As such, they argued, this concept should be considered as separate from and not subsidiary to beneficence: “First, to confuse them is to obscure distinctions that we make in ordinary moral discourse. Second, ordinary moral discourse expresses the defensible conviction that we have certain duties not to injure others that are not only distinct from but also more stringent than our duties to benefit others.” 22 The authors make the distinction that the negative duty to cause no harm should be encompassed by nonmaleficence, and the positive but not so strongly established moral duty to benefit others should constitute the core of beneficence. The authors acknowledged that other eminent scholars disagreed with the separation of nonmaleficence and beneficence, but they constructed an argument that has been upheld by the historic inclusion of nonmaleficence in most bioethics discussions following their book's original publication (the book is now its seventh edition). The book has had a significant influence on the still-evolving field of bioethics contemporary to its publication and the Belmont Report. Both authors regularly served as staff members for the Kennedy Institute Intensive Bioethics Course, and Beauchamp served as staff philosopher for the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research that produced the Belmont Report. The authors acknowledged the influence of several other members of the commission and other colleagues who contributed significantly to their deliberations as their work progressed.

US Legislative Updates, 1981

DHEW officially became the Department of Health and Human Services (HHS) in 1980, and in response to the Belmont Report, the HHS and the US Food and Drug Administration (FDA) significantly revised their protection of human subjects regulations in 1981 (45 CFR §46 and 21 CFR §50). 16 , 18 , 23

These regulations specifically address concerns related to vulnerable populations in Subparts B, C, and D, incorporating the recommendations from the National Commission. The Research on the Fetus report 24 informed Subpart B (additional protections for pregnant women, human fetuses, and neonates), Subpart C (additional protections for prisoners) reflected the recommendations in Research Involving Prisoners , 25 and Subpart D (additional protections for children) was informed by the Research Involving Children report. 26

HUMAN SUBJECTS PROTECTION OVERSIGHT

Oversight in the united states.

To this point, this review has focused on some of the historic events and documents precipitating evaluation of the ethical requirements for human subjects research in the United States and a review of the regulations that evolved from that history. The question not yet addressed is how these regulations should be enforced. As with the discussion of research ethics, the approach to enforcement of regulations also lies within the National Research Service Award Act of 1974 (Pub L No. 93-348). 17 In addition to establishing the National Commission responsible for the Belmont Report, the National Research Act elected to perpetuate the regulatory mechanism for research extant within many departments of DHEW that evolved from the US Public Health Service requirements initiated by the Surgeon General in 1966. The background of this development is described in William Curran's article, “Government Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies.” 27

This system for review of human subjects research within DHEW as described in The Institutional Guide to DHEW Policy on Protection of Human Subjects 28 became the model for institutional review boards (IRBs) that the National Research Act would require of grantees and contractees for review of research involving human subjects. The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was specifically charged with reviewing the function of IRBs and making recommendations for integrating the role of the IRB into the regulatory process to provide oversight of the application of ethical principles and of the regulations. 18

On September 1, 1978, the National Commission completed the less spectacular but equally important report, Institutional Review Boards , 29 before submitting the Belmont Report on September 30 that same year. Institutional Review Boards outlines the National Commission's concept of the ideal environment for the application of the federal regulations.

In the introduction to the report, the National Commission provides this understated assessment of the role of the IRB: “This review of proposed research by IRBs is the primary mechanism for assuring that the rights of human subjects are protected.” 29 The document outlines the ideal responsibilities of the IRB in the oversight of research to ensure that human subjects receive appropriate protections and ethical treatment for their willingness to participate in research, sometimes at no benefit to themselves. The National Commission summarized their objective as follows:

In the recommendations that follow, the Commission expresses its judgment about the ways in which those elements [that must be considered in balancing society's interests in protecting the rights of the subjects and in developing knowledge that can benefit the subjects or society as a whole] ought to be brought to bear on research practices, so that a reasonable and ethical balance of society's interests may be attained.

The Commission's deliberations begin with the premise that investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others, who are independent of the research, must share this responsibility, because investigators are always in positions of potential conflict by virtue of their concern with the pursuit of knowledge as well as the welfare of the human subjects of their research.

The Commission believes that the rights of subjects should be protected by local review committees operating pursuant to federal regulations and located in institutions where research involving human subjects is conducted. 29

The document continues this proposal and is seemingly all-inclusive in its conception of the IRB. Highlights include a list of the requirements that must be met to approve research and details for reviewing and approving the consent process, including the essential elements to be included and the safeguards that should be in place to ensure that the process is respected. Specific recommendations also address the constitution of the IRB; how it should be funded; and legal protections for the board, the process, and its members.

Most of the recommendations from the Institutional Review Boards report were incorporated into the HHS regulations—HHS being the responsible federal agency—as part of the rules revision in 1981 in response to the Belmont Report and several other publications of the National Commission. Acting independently from HHS, the FDA also adopted IRBs as a regulatory mechanism, with regulations first issued in 1981 as part of the agency's response to provisions of the National Research Act. 18 , 30

One particularly relevant recommendation of the National Commission from Institutional Review Boards remained outstanding after the changes in 1981: “Recommendation (1) (A) Federal law should be enacted or amended to authorize the Secretary of Health, Education, and Welfare to promulgate regulations governing ethical review of all research involving human subjects that is subject to federal regulation.” 29

The report notes significant “variations arising out of differences in wording, imposition of additional requirements, introduction of minor changes, etc.” among the different agencies apart from DHEW involved in research involving human subjects and expresses concern that this variability places an unnecessary burden on the individual IRBs for interpreting and properly enforcing the regulations. The National Commission's recommendation was to establish “DHEW as the sole authority” for regulations, expressing the belief that such a rule “would reduce the burden on IRBs to interpret and apply the regulations to which they are subject. Moreover, uniformity would assure a minimum level of protection to human subjects of research, no matter which federal agency is supporting the research or which entity is conducting it.” 29 Having inherited the mantle of responsibility from the now-extinct DHEW and recognizing the reality of this assessment, the newly designated HHS explored implementation of this recommendation, particularly as it related to the function of IRBs. As with most changes affecting multiple branches of government, the process became complex. In December 1981, the President's Commission for the Study of Ethical Problems in Medicine and in Biomedical and Behavioral Research, a new commission appointed by Congress in 1978, entered the fray and recommended that all federal departments and agencies adopt the HHS regulations (45 CFR §46). In addition, an ad hoc Committee for the Protection of Human Subjects—composed of representatives and ex officio members from departments and agencies that conducted, supported, or regulated research involving human subjects—was appointed in May 1982 by the president's science advisor to respond to the recommendations of this new commission. After much consideration and negotiation, these efforts were finally addressed by adoption of the Federal Policy for the Protection of Human Subjects, known as the Common Rule, in 1991 and codified in the individual regulations by 15 federal departments and agencies. Each of these agencies includes in its chapter of the Code of Federal Regulations (CFR) section numbers and language that are identical to those of the HHS codification at 45 CFR §46, Subpart A for the regulation of human subjects participation in research. The HHS regulations also include Subparts B, C, and D as additional regulations pertaining to vulnerable subjects. 16 , 31

In addition to harmonizing the regulations across agencies of the federal government, the Common Rule requires institutions that receive funds for research involving human subjects from federal agencies that are signatories to the Common Rule to certify that the research has been reviewed and approved by an IRB that meets the specific requirements for composition, for functioning, and for the criteria followed to approve research. By mandate of the Common Rule, IRBs are empowered to approve, require modifications of, or disapprove research activities and are required to conduct continuing review of ongoing research at least annually.

The FDA concurs with the Common Rule but claims special privilege in not signing on to it. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR §50 and §56 so that they conformed to the Federal Policy for the Protection of Human Subjects to the extent permitted but noted that the FDA is a regulatory agency that rarely supports or conducts research under its regulations. 32

International Oversight

With the adoption of the Common Rule, regulations for human subjects research conducted within the United States became well established, but research has never been confined by the borders of the United States. Even though a project funded by federal monetary support may have some leverage to require adherence to US regulations, significant numbers of human research subjects participate in studies well beyond the influence of the US regulations. The international norms for participation of human subjects in research evolved along a course that frequently cross-pollinated with the concepts culminating in the Common Rule. The Declaration of Helsinki was an early statement of basic tenets that should apply to all research involving human subjects, and it has continued to evolve, with updates reflecting new issues as they become relevant. While addressing the ethical concepts, the Declaration of Helsinki does not provide an organizational or regulatory framework for human subjects protection. Providing this framework on an international basis presented a challenge well beyond the challenge of harmonizing regulations across different federal agencies as was accomplished by the Common Rule. The difficulties encountered in implementing the Common Rule represent only a microcosm of the enormous task of harmonizing regulatory and organizational concepts across the borders of different cultures and political systems. However, this task was particularly relevant because of the evolution of research into an international enterprise with multicenter drug trials and the expansion of vaccine trials in children. Many of these studies are conducted by multinational contract research organizations that have access to populations of subjects with exposure to diseases that may not be widely encountered in the United States.

An argument can be made that the process for oversight of human subjects in research at the international level started in 1948 before the Declaration of Helsinki when the United Nations Educational, Scientific and Cultural Organization (UNESCO) joined with the World Health Organization (WHO) to establish a permanent Council for Coordination of International Medical Congresses, formally constituted in Brussels in 1949 as a nongovernmental organization with the purpose of facilitating “the exchange of views and scientific information in the medical sciences by securing continuity and coordination between international organizations of medical sciences, by making their work known, and by providing them with material aid where necessary.” 33 The scope of activities gradually expanded to include collaborative efforts among international medical activities in addition to the coordination of participating congresses. In 1992, the name of the council was changed to the Council for International Organizations of Medical Sciences (CIOMS), and its statutes were revised to reflect the expanded role. 33

The original council ventured into medical research by organizing a 1959 meeting in Vienna under the auspices of UNESCO and the WHO “to discuss the principles, organization and scope of ‘controlled clinical trials,’ which must be carried out if new methods or preparations used for the treatment of disease are to be accurately assessed clinically.” The executive secretary summarized the meeting: “The conference was in itself an experiment.” 34

Following this meeting, the council became much more involved in considerations regarding research and particularly the participation of human subjects in research trials, eventually publishing Proposed International Guidelines for Biomedical Research Involving Human Subjects in 1982. The purpose of the guidelines was “to indicate how the ethical principles that should guide the conduct of biomedical research involving human subjects, as set forth in the Declaration of Helsinki, could be applied, particularly in developing countries, given their socioeconomic circumstances, laws and regulations, and executive and administrative arrangements.” 35 This quote is from the background notes for International Ethical Guidelines for Biomedical Research Involving Human Subjects published in 1993 after discussion and reconsideration of the comments received in response to the proposed guidelines. 35

The publication of the guidelines in 1993, soon after the name change to CIOMS, represented a landmark for international research ethics. The steering committee included an international staff of 24 members and an even larger list of advisors and consultants. The committee was co-chaired by Robert Levine from Yale University, who was listed as a “Special Consultant” on the Belmont Report and authored the first four articles for discussion in the appendix to the Belmont Report, and John H. Bryant, an American physician with a distinguished career in international medical practice. In addition to the Declaration of Helsinki, the International Ethical Guidelines for Biomedical Research Involving Human Subjects was strongly influenced by the Belmont Report as demonstrated by the inclusion of the following text under the heading General Ethical Principles:

All research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for persons, beneficence and justice. It is generally agreed that these principles, which in the abstract have equal moral force, guide the conscientious preparation of proposals for scientific studies. 35

The guidelines acknowledge the evolution of the principles following the publication of the Belmont Report with the statement, “Beneficence further proscribes the deliberate infliction of harm on persons; this aspect of beneficence is sometimes expressed as a separate principle, non-maleficence (do no harm).” 35

The table of contents of the 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects , provided in Figure 3 , outlines the subjects the steering committee felt to be the most pertinent issues for research conducted in an international setting. In addition to the obvious influence of the Declaration of Helsinki, this document reinterprets many of the issues presented in the Belmont Report, in reports from the presidential commissions, and in 45 CFR §46, Subparts A, B, C, and D to provide an adaptable set of guidelines suitable for application across a broad spectrum of cultural and political environments. The notable exception to the similarities with the US regulations is the inclusion of a guideline titled “Compensation of Research Subjects for Accidental Injury” that provides for the following: “Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependents are entitled to material compensation. The right to compensation may not be waived.” 35 To date, no uniform program for compensation of human subjects injured in research is addressed in the US regulations.

Table of Contents, International Ethical Guidelines for Biomedical Research Involving Human Subjects, 1993 35

The International Ethical Guidelines for Biomedical Research Involving Human Subjects was updated in 2002, and CIOMS continues its efforts to revise the guidelines as dictated by changes in research requiring human subjects.

THE GUATEMALA SEXUALLY TRANSMITTED DISEASES STUDY

All the efforts described to this point promoted regulations and procedures based on an ethically sound approach to protecting human subjects who, by consent or proxy, will be participating in research. The ethics of the research environment seems to have improved as a result of these efforts both in the United States and internationally. Notable instances of particularly egregious studies have come to light since the publication of the Belmont Report, but most of these studies originated before that document was issued. One study in particular raised eyebrows for its similarity to the transgressions committed in the Tuskegee study and, after investigation, was found to have ties to the Tuskegee study.

In October 2010, the United States disclosed that the US Public Health Service sponsored studies of sexually transmitted diseases in Guatemala beginning in 1946. This exposé began with the discovery of documents among papers donated by Dr John Cutler to the library at the University of Pittsburgh. Before retiring, Cutler was on the faculty at the university's School of Public Health following a long career in the US Public Health Service where he had been one of the staff members involved with the Tuskegee study. Hoping to gain insight into the Tuskegee study, Dr Susan Reverby from Wellesley was reviewing Cutler's papers when she came across previously unknown information about experiments investigating sexually transmitted diseases in Guatemala that Cutler and his associates conducted. 36 An account in the American Journal of Public Health reports that “… more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases” and many were never treated. 37

When the details of these experiments came to light, they precipitated an apology from President Barack Obama and specific directives to the Presidential Commission for the Study of Bioethical Issues, a commission appointed by Obama, to “convene a panel to conduct, beginning in January 2011, a thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government. I also request that the Commission oversee a thorough fact-finding investigation into the specifics of the U.S. Public Health Service Sexually Transmitted Diseases Inoculation Study” ( Figure 4 ). 38

Directive from President Barack Obama to investigate the Guatemalan studies, 2010 38

The Presidential Commission's first report, “ Ethically Impossible” STD Research in Guatemala from 1946 to 1948 , provides a detailed account of the history surrounding the Guatemala studies and all of the supporting evidence. In the preface, the Presidential Commission reports, “With dual responsibilities to give a full and fair accounting of events largely hidden from history for nearly 65 years and also provide an assessment of the current system, the Commission decided to publish two reports. This is the first report, a historical account and ethical assessment of the Guatemala experiments.” 38

The specific political circumstances in which the experiments were conceived and carried out is critical to gaining some understanding of how ethically questionable research, however ill-conceived, was carried out by people who most probably had good intentions. The significance of the deleterious effects of sexually transmitted diseases among troops in World War II and how those effects precipitated the experiments are difficult to understand in today's world of effective antibiotics. In the 1940s wartime environment, however, understanding all aspects of sexually transmitted diseases was perceived as a crucial aspect of the military's ability to field an effective fighting force for the war in Europe. The experiments must be viewed in this historic context to understand the powerful motivation behind the studies.

The “ Ethically Impossible ” report includes an excerpt from a 1943 letter from Dr Joseph Earle Moore, Chair of the Subcommittee on Venereal Diseases under the National Research Council, to A. N. Richards, Chair of the Medical Research Committee of the Office of Scientific Research and Development, in which Moore wrote that he expected “approximately 350,000 fresh infections with gonorrhea [in the Armed Forces], [which] will account for 7,000,000 lost man days per year, the equivalent of putting out of action for a full year the entire strength of two full armored divisions or of ten aircraft carriers.” 38 Moore estimated that the cost of treating the anticipated infections would be $34 million, equivalent to approximately $440 million today, adjusted for inflation.

Within this context, serious planning to meet the challenge of understanding and treating sexually transmitted diseases appears to have coalesced at the national level in 1942. Planning for these studies continued through the following year, with one of the principals suggesting “the possibility of using federal prisoners, Army prisoners, or conscientious objectors as an alternative” for research subjects. 38 In 1943, experiments began at the US Penitentiary in Terre Haute, IN, that continued for 2 years. The focus of the experiments was on efforts to infect prisoners with Neisseria gonorrhoeae to test various methods for prophylaxis and treatment. Isolates of bacteria were applied directly to the penises of subjects in an effort to reliably infect the “volunteers.” However, the failure to reliably infect subjects in this fashion clearly indicated that studies of prophylactic techniques would not be possible with this approach, leading to consideration of other options.

The studies were performed under the direction of Dr John F. Mahoney, then head of the US Public Health Service/Venereal Disease Research Laboratory (VDRL) set up within the US Marine Hospital in Staten Island, NY. Mahoney directed the Terra Haute prison studies from his Staten Island laboratory, while 28-year-old Dr Cutler ran the studies at the prison. Following the end of World War II in 1945, the military support for the studies was less enthusiastic, but the Public Health Service remained committed to supporting the research with plans to move the research to Guatemala. A 1947 article Mahoney published in the Journal of Venereal Disease Information provides some insight into why the studies were moved: “It has been considered impractical to work out, under postwar conditions in the United States, the solution of certain phases concerned with the prevention and treatment of syphilis. These problems are largely concerned with the development of an effective prophylactic agent for both gonorrhea and syphilis and the prolonged observation of patients treated with penicillin for early syphilis. Because of the relatively fixed character of the population and because of the highly cooperative attitude of the officials, both civil and military, an experimental laboratory in Guatemala City has been established….” 39

As fate would have it, a Guatemalan physician named Funes, who had served a fellowship at the VDRL and returned to Guatemala, was essential to the transition of the studies to his country. In August 1946, Cutler transitioned from Terra Haute to Guatemala at Funes's urging. Cutler staffed a clinic that provided the regular health inspections required for registered sex workers and suggested that the facility provide an environment of “normal exposure” through which sexually transmitted diseases could be more predictably transmitted. The studies in Guatemala evaluated possible prophylactic intervention “in cooperation with the Guatemalan Venereal Disease Control Department” that Funes directed and the local penitentiary “where exposure of volunteers to infected prostitutes would provide the testing opportunities.” 38 Enrolling prisoners, a contained and restricted population, after they had had sexual intercourse with commercial sex workers known to be infected with sexually transmitted diseases, promised to establish, according to Cutler, a “rapid and unequivocal answer as to the value of various prophylactic techniques” through the preferred technique of “normal exposure.” 38

After beginning with studies of “normal exposure” in prisoners, Cutler expanded the population of research subjects to include patients in a psychiatric hospital and again tried artificial means of infection, including scarification—mechanically damaging the skin and mucous membranes of the penis—to enhance the likelihood of infecting the subject. An even more aggressive study included at least 7 women in a psychiatric institution who were infected by the injection of syphilis specimens directly into the subarachnoid space surrounding the brain. Only 5 of them later received medical therapy. 38 In addition, studies to follow the serology of children in a large orphanage were undertaken to better understand the specificity of tests for sexually transmitted diseases, an additional goal of the Guatemalan studies.

Studies in which subjects were intentionally infected were completed in the later months of 1948, and Cutler left Guatemala in December 1948 to join a WHO Disease Demonstration Team in India. From April 1949 to July 1950, this team worked to establish a venereal disease control demonstration in various parts of India and teach advanced methods of control for sexually transmitted diseases. Meanwhile, the US Public Health Service hired Funes and another Guatemalan physician, Dr Salvado, to continue “the observation of certain of the patient groups” after Cutler left Guatemala. Funes's staff collected data on residents of the orphanage, inmates of the penitentiary, individuals from the psychiatric hospital, schoolchildren, and the members of “various Indian tribes in the vicinity of Guatemala” who had participated in the experiments. Funes was hired to “advise concerning the clinical examinations of treated patients, their re-treatment as may be required, the collection of blood specimens for serologic examinations at periodic intervals, the preparation and shipment of all blood specimens collected for serologic examination” to the United States, and “the submission of such reports as may be necessary for the completion of the study of this patient group.” 38 Based on the one report available in the Cutler Documents, Funes and his staff followed approximately 248 people from the mental institution, completing 243 blood draws and 170 lumbar punctures. Several of those subjects tested positive for syphilis during the follow-up experiments. The subjects from the psychiatric hospital were followed until at least 1953. The published work resulting from the Guatemala experiments also indicates that Funes continued to do serological testing on the children at the orphanage until at least 1949.

The experiments in Terra Haute were conducted and supported by many of the same people involved in the Guatemala experiments with the same goal of finding suitable prophylaxes for sexually transmitted diseases. However, throughout their discussion of the background leading to the experiments in the United States and the subsequent Guatemalan experiments, the Presidential Commission provides details of concerns voiced among those planning the studies. These details construct a compelling argument that all along the way there was an undercurrent of concern that the studies proposed were at the least controversial, most probably unethical, and in some instances arguably illegal. The Presidential Commission reached the conclusion that “Conducting the experiments in Guatemala provided an opportunity to work with reduced concern for some of the key obstacles associated with the Terre Haute experiments: fear of adverse legal consequences and bad publicity.” In a footnote to the report, the authors point out that “These concerns followed the researchers to Guatemala, however, as evidenced by some of their efforts to limit and restrict access to information about the work.” 38

The Presidential Commission summarized their findings as follows: “In the Commission's view, the Guatemala experiments involved unconscionable violations of ethics, even as judged against the researchers’ own understanding of the practices and requirements of medical ethics of the day.” The report concludes

Although some individuals are more blameworthy than others, the blame for this episode cannot be said to fall solely on the shoulders of one or two individuals. The unconscionable events that unfolded in Guatemala in the years 1946 to 1948 also represented an institutional failure of the sort that modern requirements of transparency and accountability are designed to prevent. In the final analysis, institutions are comprised of individuals who, however flawed, are expected to exercise sound judgment in the pursuit of their institutional mission. This is all the more true and important when those individuals hold privileged and powerful roles as professionals and public officials. One lesson of the Guatemala experiments, never to take ethics for granted, let alone confuse ethical principles with burdensome obstacles to be overcome or evaded, is a sobering one for our own and all subsequent generations. We should be ever vigilant to ensure that such reprehensible exploitation of our fellow human beings is never repeated. 38

The second charge from President Obama to the Presidential Commission was to provide a “thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.” The Presidential Commission addressed this directive in their report Moral Science: Protecting Participants in Human Subjects Research that was completed in December 2011. 40

Regarding whether the regulations would prevent abuses similar to the studies in Guatemala, the Commission noted, “Existing evidence suggests both that the rules governing federal research today adequately guard against abuses analogous to those perpetrated in Guatemala in the 1940s and that current regulations generally appear to protect people from avoidable harm or unethical treatment, insofar as is feasible given limited resources, no matter where U.S.-supported research occurs.” 40 The report summary continued as follows:

The current U.S. system provides substantial protections for the health, rights, and welfare of research subjects and, in general, serves to “protect people from harm or unethical treatment” when they volunteer to participate as subjects in scientific studies supported by the federal government. However, because of the currently limited ability of some governmental agencies to identify basic information about all of their human subjects research, the Commission cannot say that all federally funded research provides optimal protections against avoidable harms and unethical treatment. The Commission finds significant room for improvement in several areas where, for example, immediate changes can be made to increase accountability and thereby reduce the likelihood of harm or unethical treatment. 40

The report outlines the Presidential Commission's observations and recommendations based on a thorough review of federally funded research, including studies that may involve human subjects in other countries. One issue the Commission raised was the general lack of accessibility to data: “there is no ready source that comprehensively describes its [the federally funded human research enterprise] basic characteristics, such as level of funding, or number of studies, subjects, or geographic locations. Instead, what exists are isolated pockets of information and some descriptive summaries.” 40 This difficulty in acquiring information prompted the Presidential Commission's first recommendation to improve accountability through public access: “accountability can and should be refined through improving access to basic information about the scope and volume of human subjects research funded by the government.” The commission cites precedent for this recommendation from the Institute of Medicine–issued Responsible Research: A Systems Approach to Protecting Research Participants , with its recommendation to extend the oversight system to all research, regardless of funding source or research setting. 41

Treatment and compensation for research-related injuries were also identified as an issue of concern, a subject that has been scrutinized regularly in past discussions as human research protection has evolved. Obama's Commission noted that this issue still required attention at the time of their review, pointing out that most other developed countries require sponsors, investigators, or others engaged in research to provide treatment or reimbursement free of charge to the subject for research-related injury or illness. As discussed earlier, one of the deviations from the general agreement between CIOMS and US regulations is the recommendation for subject compensation in the CIOMS guidelines. The Presidential Commission “draws a bright line affirming the view of most bioethicists and others, including the majority of nations supporting human subjects research around the globe, that human subjects should not individually bear the costs of care required to treat harms resulting directly from that research.” 40 Recognizing that previous bioethics commissions and other advisory bodies had opined in favor of compensation or treatment for research-related injuries with relative silence by the government, the Commission advocated a response as to reasons for changing or maintaining the status quo. This issue remains open with no progress as this article is being written.

The Commission also asked that the OHRP examine, recognize, and define when protections delineated in foreign laws and regulations are accepted as equivalent to US regulations and exercise its longstanding authority to recognize these protections when available. Protections offered by international partners have been a source of confusion, as the federal regulations state that equivalent protections from international studies should be accommodated but do not provide guidance for how they should be defined. This directive has been reevaluated several times since its inception, including a specific request from the United Kingdom in 2007 to provide a determination of equivalence for human research protections afforded by UK regulations. As of the Commission's report in 2011, the OHRP had not formally recognized any country's protections as equivalent.

The Commission also noted that the FDA, while not signatory to the Common Rule, does adhere to the regulations at 45 CFR §46, Subpart A whenever possible and accepts data from foreign studies that comply with certain international standards for human subjects protection, such as studies that abide by good clinical practice, the Declaration of Helsinki, or certain host country regulations. This practice should provide a model to develop a system for recognizing equivalent protections as currently regulated by provisions in the Common Rule.

In its final recommendation, Promoting Current Federal Reform Efforts, the Presidential Commission called for broad reform of federal research rules and procedures beyond simply addressing equivalent protections.

The Commission supports the federal government's proposed reforms to:

a) Restructure research oversight to appropriately calibrate the level and intensity of the review activities with the level of risk to human subjects;

b) Eliminate continuing review for certain lower-risk studies and regularly update the list of research categories that may undergo expedited review;

c) Reduce unnecessary, duplicative, or redundant institutional review board review in multi-site studies. Regardless of the process used to review and approve studies, institutions should retain responsibility for ensuring that human subjects are protected at their location as protection of human subjects includes much more than institutional review board review. The use of a single institutional review board of record should be made the regulatory default unless institutions or investigators have sufficient justification to act otherwise;

d) Make available standardized consent form templates with clear language understandable to subjects;

e) Harmonize the Common Rule and existing regulations of the Food and Drug Administration, and require that all federal agencies conducting human subjects research adopt human subjects regulations that are consistent with the ethical requirements of the Common Rule; and

f) Work toward developing an interoperable or compatible data collection system for adverse event reporting across the federal government. 40

Most of these provisions were included in the revisions to the Common Rule that updated the original provisions from 1991 and were effective January 21, 2019, with the exception of staged implementation of single IRB review for multisite studies. Twenty federal agencies follow the Common Rule, with the notable exception of the FDA. So far, no official indication of the FDA's intent has been provided, although the expectation is that some effort will be made to harmonize the regulations—at least in a similar fashion as previous agreements.

OTHER HUMAN SUBJECTS PROTECTION FAILURES

This exposition of how we have arrived at the current rules and regulations for protecting human subjects who participate in research is lengthy but is at best an outline. Even this abbreviated history should elicit an appreciation of the complexity of the ethics surrounding protection of human subjects in research. A fair question is whether these provisions have significantly altered the landscape since Dr Beecher published his concerns in the New England Journal of Medicine in 1966. A cursory review turns up a few exceptions to the relative safety afforded by the current protections, with three that are particularly instructive.

Jesse Gelsinger

Jesse Gelsinger had just turned 18, the legal age for consent, when he volunteered in 1999 for a phase 1 gene therapy study designed for treatment of ornithine transcarbamylase (OTC) deficiency. Phase 1 studies are designed primarily to determine the appropriate dose of a drug. Gelsinger was born with a mild form of OTC that was well controlled by diet and drug therapy; he had minimal risk of serious complications from the disease as long as he followed his treatment protocol. He did not stand to benefit significantly from his participation in the phase 1 study but felt that he should volunteer because of the knowledge that might benefit others.

Gelsinger died 4 days after receiving an experimental therapy consisting of a gene attached to an adenovirus that would theoretically serve as a delivery system to insert the new gene into the DNA of his liver cells. The death was unexpected in a relatively healthy 18-year-old, and the outcome precipitated a long and contentious investigation into how the protections that should have prevented Gelsinger from participating in the study were circumvented or ignored. The investigation uncovered questions regarding (1) information that should have been included in the consent form, (2) the actual risk posed by the study based on complications from similar studies that were not disclosed in reports to regulatory bodies, (3) why Gelsinger was enrolled in the study in violation of the protocol's inclusion/exclusion criteria, (4) the potential risk/benefit analysis based on the mild nature of his disease that would argue against his participation, and (5) an undisclosed conflict of interest for the director of the gene studies program that may have clouded decisions at critical points during conduct of the study. 42 - 45

Examination of this study demonstrates that the protections afforded to subjects are well established but still depend on the assumption that the individuals responsible for every step of the evaluation and approval of studies and those who actually conduct the research all perform reliably in their roles.

Johns Hopkins Lead Abatement Study

Another notable case revolves around the issues of appropriate consent, appropriate risks for children (or any vulnerable population), and disclosure of results obtained in research studies. The Kennedy Krieger Institute (KKI), an affiliate of Johns Hopkins Children's Center, conducted a study evaluating the effectiveness of lead abatement programs in low-income housing in Baltimore, MD during the 1990s. The study recruited families to live in houses either untouched or treated with different abatement techniques to determine which processes were most effective in protecting children from the significant neurologic effects of elevated lead levels that were endemic among children living in low-income housing in Baltimore. The goal was “to find a relatively inexpensive and effective method for reducing—though not eliminating—the amount of lead in children's homes and thereby reducing the devastating effect of lead exposure on children's brains.” 46 A total of 108 families with young children were recruited to live in houses with lead levels ranging from none to levels just below the existing legal limit, and the children's serum lead levels were monitored. In two homes, the lead levels in the children crossed into toxic levels, but the families were not informed or advised to move out of the toxic environment. Eventually, a lawsuit was filed on behalf of the two children, and it raised significant ethical questions surrounding informed consent, appropriate risks, and disclosure of results that are reviewed at length in the article “With the Best Intentions: Lead Research and the Challenge to Public Health.” 46 The Maryland Court of Appeals opinion equated the multiyear lead study with the Tuskegee study in its egregious disregard for research ethics in a vulnerable population.

Ellen Roche

Ellen Roche was a healthy 24-year-old laboratory technician at the Johns Hopkins Asthma and Allergy Center. She volunteered to take part in a 2001 lung function physiology experiment in which normal pulmonary function in healthy volunteers would be manipulated by inhalation of hexamethonium, a compound that interferes with normal nervous system interaction with the lungs to mimic a mild asthma attack. Although it had been used in the 1950s to treat hypertension, hexamethonium fell into disuse as more effective drugs became available, and the FDA withdrew approval in 1972. Of note, hexamethonium was never approved as an inhaled medication. Roche was the fourth patient to receive hexamethonium in the trial. At least one previous subject had had mild persistent respiratory symptoms that the investigator dismissed as a cold. Roche became very ill, with significant pulmonary abnormalities presenting within 24 hours. The symptoms progressed to multisystem organ failure, and she died within a month. 47 , 48

The ensuing investigation turned up several concerns:

• The literature search relied on PubMed and one contemporary textbook of pulmonary medicine to explore the potential use of hexamethonium for the purpose proposed in the research plan. Neither source revealed any indication of concerns, although other databases and older textbooks warned of significant pulmonary complications associated with hexamethonium.
• No request was made to determine if the FDA required an investigational new drug application, even though the medication was no longer approved and had never been approved as an inhalational drug.
• The consent form referred to hexamethonium as a medication but failed to mention that FDA approval had been withdrawn.
• A few subjects included in previous studies used inhaled hexamethonium with no mention of problems in the subsequent publications, but two subjects did have significant difficulties that were not reported as the investigator did not consider them related to the drug.
• The hexamethonium used in the study was of chemical grade and was not prepared as a pharmaceutical agent. 47 , 48

This list is not complete and raises many concerns, but the focus of the investigation became the lack of adequate research to confirm that the compound used to induce asthma symptoms was safe. The responsibility for this failure primarily attached to the investigator, with additional concern focusing on a review process that failed to follow proper procedures for approval of the protocol. During the follow-up, several articles from the 1950s reporting that hexamethonium could cause fatal lung inflammation similar to the pulmonary complications leading to the demise of Ellen Roche were identified. PubMed's coverage of the literature starts in the mid-1960s. In addition, review of the FDA records related to the withdrawal of hexamethonium in 1972 cited the drug's “substantial potential toxicity” as one element leading to the decision. 48

The examples of ethical issues from history and the scarcity of contemporary examples demonstrate that regulations for the protection of humans participating in research have evolved in a way that minimizes the probability of harm to subjects choosing to participate in research. These examples also reinforce the importance of individual responsibility to faithfully execute the requirements of their assigned roles. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Furthermore, these examples support the argument that no amount of regulation or oversight can completely remove the variable of individual failures to adhere to the rules or accept the responsibility associated with their role in research that may precipitate serious unexpected consequences. The rules and expectations for those charged with the review, administration, and performance of research requiring human subjects can only minimize the probability that these instances will occur. The point at which the primary responsibility of protecting human subjects from preventable harm deviates to focus on some other aspect of the research that leads to harm is rarely predictable. Simplified to the world of Monty Python, “Nobody expects the Spanish Inquisition!”

ACKNOWLEDGMENTS

The author has no financial or proprietary interest in the subject matter of this article.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Systems-Based Practice.

• 30 Most Unethical Psychology Human Experiments

Disturbing human experiments aren’t something the average person thinks too much about. Rather, the progress achieved in the last 150 years of human history is an accomplishment we’re reminded of almost daily. Achievements made in biomedicine and the f ield of psychology mean that we no longer need to worry about things like deadly diseases or masturbation as a form of insanity. For better or worse, we have developed more effective ways to gather information, treat skin abnormalities, and even kill each other. But what we are not constantly reminded of are the human lives that have been damaged or lost in the name of this progress. The following is a list of the 30 most disturbing human experiments in history.

30. The Tearoom Sex Study

Image Source Sociologist Laud Humphreys often wondered about the men who commit impersonal sexual acts with one another in public restrooms. He wondered why “tearoom sex” — fellatio in public restrooms — led to the majority of homosexual arrests in the United States. Humphreys decided to become a “watchqueen” (the person who keeps watch and coughs when a cop or stranger get near) for his Ph.D. dissertation at Washington University. Throughout his research, Humphreys observed hundreds of acts of fellatio and interviewed many of the participants. He found that 54% of his subjects were married, and 38% were very clearly neither bisexual or homosexual. Humphreys’ research shattered a number of stereotypes held by both the public and law enforcement.

29. Prison Inmates as Test Subjects

Image Source In 1951, Dr. Albert M. Kligman, a dermatologist at the University of Pennsylvania and future inventor of Retin-A, began experimenting on inmates at Philadelphia’s Holmesburg Prison. As Kligman later told a newspaper reporter, “All I saw before me were acres of skin. It was like a farmer seeing a field for the first time.” Over the next 20 years, inmates willingly allowed Kligman to use their bodies in experiments involving toothpaste, deodorant, shampoo, skin creams, detergents, liquid diets, eye drops, foot powders, and hair dyes. Though the tests required constant biopsies and painful procedures, none of the inmates experienced long-term harm.

28. Henrietta Lacks

Image Source In 1955, Henrietta Lacks, a poor, uneducated African-American woman from Baltimore, was the unwitting source of cells which where then cultured for the purpose of medical research. Though researchers had tried to grow cells before, Henrietta’s were the first successfully kept alive and cloned. Henrietta’s cells, known as HeLa cells, have been instrumental in the development of the polio vaccine, cancer research, AIDS research, gene mapping, and countless other scientific endeavors. Henrietta died penniless and was buried without a tombstone in a family cemetery. For decades, her husband and five children were left in the dark about their wife and mother’s amazing contribution to modern medicine.

27. Project QKHILLTOP

Image Source In 1954, the CIA developed an experiment called Project QKHILLTOP to study Chinese brainwashing techniques, which they then used to develop new methods of interrogation. Leading the research was Dr. Harold Wolff of Cornell University Medical School. After requesting that the CIA provide him with information on imprisonment, deprivation, humiliation, torture, brainwashing, hypnoses, and more, Wolff’s research team began to formulate a plan through which they would develop secret drugs and various brain damaging procedures. According to a letter he wrote, in order to fully test the effects of the harmful research, Wolff expected the CIA to “make available suitable subjects.”

26. Stateville Penitentiary Malaria Study

Image Source During World War II, malaria and other tropical diseases were impeding the efforts of American military in the Pacific. In order to get a grip, the Malaria Research Project was established at Stateville Penitentiary in Joliet, Illinois. Doctors from the University of Chicago exposed 441 volunteer inmates to bites from malaria-infected mosquitos. Though one inmate died of a heart attack, researchers insisted his death was unrelated to the study. The widely-praised experiment continued at Stateville for 29 years, and included the first human test of Primaquine, a medication still used in the treatment of malaria and Pneumocystis pneumonia.

25. Emma Eckstein and Sigmund Freud

Image Source Despite seeking the help of Sigmund Freud for vague symptoms like stomach ailments and slight depression, 27-year old Emma Eckstein was “treated” by the German doctor for hysteria and excessive masturbation, a habit then considered dangerous to mental health. Emma’s treatment included a disturbing experimental surgery in which she was anesthetized with only a local anesthetic and cocaine before the inside of her nose was cauterized. Not surprisingly, Emma’s surgery was a disaster. Whether Emma was a legitimate medical patient or a source of more amorous interest for Freud, as a recent movie suggests, Freud continued to treat Emma for three years.

24. Dr. William Beaumont and the Stomach

Image Source In 1822, a fur trader on Mackinac Island in Michigan was accidentally shot in the stomach and treated by Dr. William Beaumont. Despite dire predictions, the fur trader survived — but with a hole (fistula) in his stomach that never healed. Recognizing the unique opportunity to observe the digestive process, Beaumont began conducting experiments. Beaumont would tie food to a string, then insert it through the hole in the trader’s stomach. Every few hours, Beaumont would remove the food to observe how it had been digested. Though gruesome, Beaumont’s experiments led to the worldwide acceptance that digestion was a chemical, not a mechanical, process.

23. Electroshock Therapy on Children

Image Source In the 1960s, Dr. Lauretta Bender of New York’s Creedmoor Hospital began what she believed to be a revolutionary treatment for children with social issues — electroshock therapy. Bender’s methods included interviewing and analyzing a sensitive child in front of a large group, then applying a gentle amount of pressure to the child’s head. Supposedly, any child who moved with the pressure was showing early signs of schizophrenia. Herself the victim of a misunderstood childhood, Bender was said to be unsympathetic to the children in her care. By the time her treatments were shut down, Bender had used electroshock therapy on over 100 children, the youngest of whom was age three.

22. Project Artichoke

Image Source In the 1950s, the CIA’s Office of Scientific Intelligence ran a series of mind control projects in an attempt to answer the question “Can we get control of an individual to the point where he will do our bidding against his will and even against fundamental laws of nature?” One of these programs, Project Artichoke, studied hypnosis, forced morphine addiction, drug withdrawal, and the use of chemicals to incite amnesia in unwitting human subjects. Though the project was eventually shut down in the mid-1960s, the project opened the door to extensive research on the use of mind-control in field operations.

21. Hepatitis in Mentally Disabled Children

Image Source In the 1950s, Willowbrook State School, a New York state-run institution for mentally handicapped children, began experiencing outbreaks of hepatitis. Due to unsanitary conditions, it was virtually inevitable that these children would contract hepatitis. Dr. Saul Krugman, sent to investigate the outbreak, proposed an experiment that would assist in developing a vaccine. However, the experiment required deliberately infecting children with the disease. Though Krugman’s study was controversial from the start, critics were eventually silenced by the permission letters obtained from each child’s parents. In reality, offering one’s child to the experiment was oftentimes the only way to guarantee admittance into the overcrowded institution.

20. Operation Midnight Climax

Image Source Initially established in the 1950s as a sub-project of a CIA-sponsored, mind-control research program, Operation Midnight Climax sought to study the effects of LSD on individuals. In San Francisco and New York, unconsenting subjects were lured to safehouses by prostitutes on the CIA payroll, unknowingly given LSD and other mind-altering substances, and monitored from behind one-way glass. Though the safehouses were shut down in 1965, when it was discovered that the CIA was administering LSD to human subjects, Operation Midnight Climax was a theater for extensive research on sexual blackmail, surveillance technology, and the use of mind-altering drugs on field operations.

19. Study of Humans Accidentally Exposed to Fallout Radiation

Image Source The 1954 “Study of Response of Human Beings exposed to Significant Beta and Gamma Radiation due to Fall-out from High-Yield Weapons,” known better as Project 4.1, was a medical study conducted by the U.S. of residents of the Marshall Islands. When the Castle Bravo nuclear test resulted in a yield larger than originally expected, the government instituted a top secret study to “evaluate the severity of radiation injury” to those accidentally exposed. Though most sources agree the exposure was unintentional, many Marshallese believed Project 4.1 was planned before the Castle Bravo test. In all, 239 Marshallese were exposed to significant levels of radiation.

18. The Monster Study

Image Source In 1939, University of Iowa researchers Wendell Johnson and Mary Tudor conducted a stuttering experiment on 22 orphan children in Davenport, Iowa. The children were separated into two groups, the first of which received positive speech therapy where children were praised for speech fluency. In the second group, children received negative speech therapy and were belittled for every speech imperfection. Normal-speaking children in the second group developed speech problems which they then retained for the rest of their lives. Terrified by the news of human experiments conducted by the Nazis, Johnson and Tudor never published the results of their “Monster Study.”

17. Project MKUltra

Image Source Project MKUltra is the code name of a CIA-sponsored research operation that experimented in human behavioral engineering. From 1953 to 1973, the program employed various methodologies to manipulate the mental states of American and Canadian citizens. These unwitting human test subjects were plied with LSD and other mind-altering drugs, hypnosis, sensory deprivation, isolation, verbal and sexual abuse, and various forms of torture. Research occurred at universities, hospitals, prisons, and pharmaceutical companies. Though the project sought to develop “chemical […] materials capable of employment in clandestine operations,” Project MKUltra was ended by a Congress-commissioned investigation into CIA activities within the U.S.

16. Experiments on Newborns

Image Source In the 1960s, researchers at the University of California began an experiment to study changes in blood pressure and blood flow. The researchers used 113 newborns ranging in age from one hour to three days old as test subjects. In one experiment, a catheter was inserted through the umbilical arteries and into the aorta. The newborn’s feet were then immersed in ice water for the purpose of testing aortic pressure. In another experiment, up to 50 newborns were individually strapped onto a circumcision board, then tilted so that their blood rushed to their head and their blood pressure could be monitored.

15. The Aversion Project

Image Source In 1969, during South Africa’s detestable Apartheid era, thousands of homosexuals were handed over to the care of Dr. Aubrey Levin, an army colonel and psychologist convinced he could “cure” homosexuals. At the Voortrekkerhoogte military hospital near Pretoria, Levin used electroconvulsive aversion therapy to “reorientate” his patients. Electrodes were strapped to a patient’s upper arm with wires running to a dial calibrated from 1 to 10. Homosexual men were shown pictures of a naked man and encouraged to fantasize, at which point the patient was subjected to severe shocks. When Levin was warned that he would be named an abuser of human rights, he emigrated to Canada where he currently works at a teaching hospital.

14. Medical Experiments on Prison Inmates

Image Source Perhaps one benefit of being an inmate at California’s San Quentin prison is the easy access to acclaimed Bay Area doctors. But if that’s the case, then a downside is that these doctors also have easy access to inmates. From 1913 to 1951, Dr. Leo Stanley, chief surgeon at San Quentin, used prisoners as test subjects in a variety of bizarre medical experiments. Stanley’s experiments included sterilization and potential treatments for the Spanish Flu. In one particularly disturbing experiment, Stanley performed testicle transplants on living prisoners using testicles from executed prisoners and, in some cases, from goats and boars.

13. Sexual Reassignment

Image Source In 1965, Canadian David Peter Reimer was born biologically male. But at seven months old, his penis was accidentally destroyed during an unconventional circumcision by cauterization. John Money, a psychologist and proponent of the idea that gender is learned, convinced the Reimers that their son would be more likely to achieve a successful, functional sexual maturation as a girl. Though Money continued to report only success over the years, David’s own account insisted that he had never identified as female. He spent his childhood teased, ostracized, and seriously depressed. At age 38, David committed suicide by shooting himself in the head.

12. Effect of Radiation on Testicles

Image Source Between 1963 and 1973, dozens of Washington and Oregon prison inmates were used as test subjects in an experiment designed to test the effects of radiation on testicles. Bribed with cash and the suggestion of parole, 130 inmates willingly agreed to participate in the experiments conducted by the University of Washington on behalf of the U.S. government. In most cases, subjects were zapped with over 400 rads of radiation (the equivalent of 2,400 chest x-rays) in 10 minute intervals. However, it was much later that the inmates learned the experiments were far more dangerous than they had been told. In 2000, the former participants settled a $2.4 million class-action settlement from the University.

11. Stanford Prison Experiment

Image Source Conducted at Stanford University from August 14-20, 1971, the Stanford Prison Experiment was an investigation into the causes of conflict between military guards and prisoners. Twenty-four male students were chosen and randomly assigned roles of prisoners and guards. They were then situated in a specially-designed mock prison in the basement of the Stanford psychology building. Those subjects assigned to be guards enforced authoritarian measures and subjected the prisoners to psychological torture. Surprisingly, many of the prisoners accepted the abuses. Though the experiment exceeded the expectations of all of the researchers, it was abruptly ended after only six days.

10. Syphilis Experiments in Guatemala

Image Source From 1946 to 1948, the United States government, Guatemalan president Juan José Arévalo, and some Guatemalan health ministries, cooperated in a disturbing human experiment on unwitting Guatemalan citizens. Doctors deliberately infected soldiers, prostitutes, prisoners, and mental patients with syphilis and other sexually transmitted diseases in an attempt to track their untreated natural progression. Treated only with antibiotics, the experiment resulted in at least 30 documented deaths. In 2010, the United States made a formal apology to Guatemala for their involvement in these experiments.

9. Tuskegee Syphilis Study

Image Source In 1932, the U.S. Public Health Service began working with the Tuskegee Institute to track the natural progression of untreated syphilis. Six hundred poor, illiterate, male sharecroppers were found and hired in Macon County, Alabama. Of the 600 men, only 399 had previously contracted syphilis, and none were told they had a life threatening disease. Instead, they were told they were receiving free healthcare, meals, and burial insurance in exchange for participating. Even after Penicillin was proven an effective cure for syphilis in 1947, the study continued until 1972. In addition to the original subjects, victims of the study included wives who contracted the disease, and children born with congenital syphilis. In 1997, President Bill Clinton formally apologized to those affected by what is often called the “most infamous biomedical experiment in U.S. history.”

8. Milgram Experiment

In 1961, Stanley Milgram, a psychologist at Yale University, began a series of social psychology experiments that measured the willingness of test subjects to obey an authority figure. Conducted only three months after the start of the trial of German Nazi war criminal Adolf Eichmann, Milgram’s experiment sought to answer the question, “Could it be that Eichmann and his million accomplices in the Holocaust were just following orders?” In the experiment, two participants (one secretly an actor and one an unwitting test subject) were separated into two rooms where they could hear, but not see, each other. The test subject would then read a series of questions to the actor, punishing each wrong answer with an electric shock. Though many people would indicate their desire to stop the experiment, almost all subjects continued when they were told they would not be held responsible, or that there would not be any permanent damage.

7. Infected Mosquitos in Towns

In 1956 and 1957, the United States Army conducted a number of biological warfare experiments on the cities of Savannah, Georgia and Avon Park, Florida. In one such experiment, millions of infected mosquitos were released into the two cities, in order to see if the insects could spread yellow fever and dengue fever. Not surprisingly, hundreds of researchers contracted illnesses that included fevers, respiratory problems, stillbirths, encephalitis, and typhoid. In order to photograph the results of their experiments, Army researchers pretended to be public health workers. Several people died as a result of the research.

6. Human Experimentation in the Soviet Union

Beginning in 1921 and continuing for most of the 21st century, the Soviet Union employed poison laboratories known as Laboratory 1, Laboratory 12, and Kamera as covert research facilities of the secret police agencies. Prisoners from the Gulags were exposed to a number of deadly poisons, the purpose of which was to find a tasteless, odorless chemical that could not be detected post mortem. Tested poisons included mustard gas, ricin, digitoxin, and curare, among others. Men and women of varying ages and physical conditions were brought to the laboratories and given the poisons as “medication,” or part of a meal or drink.

5. Human Experimentation in North Korea

Image Source Several North Korean defectors have described witnessing disturbing cases of human experimentation. In one alleged experiment, 50 healthy women prisoners were given poisoned cabbage leaves — all 50 women were dead within 20 minutes. Other described experiments include the practice of surgery on prisoners without anesthesia, purposeful starvation, beating prisoners over the head before using the zombie-like victims for target practice, and chambers in which whole families are murdered with suffocation gas. It is said that each month, a black van known as “the crow” collects 40-50 people from a camp and takes them to an known location for experiments.

4. Nazi Human Experimentation

Image Source Over the course of the Third Reich and the Holocaust, Nazi Germany conducted a series of medical experiments on Jews, POWs, Romani, and other persecuted groups. The experiments were conducted in concentration camps, and in most cases resulted in death, disfigurement, or permanent disability. Especially disturbing experiments included attempts to genetically manipulate twins; bone, muscle, and nerve transplantation; exposure to diseases and chemical gasses; sterilization, and anything else the infamous Nazi doctors could think up. After the war, these crimes were tried as part of the Nuremberg Trial and ultimately led to the development of the Nuremberg Code of medical ethics.

3. Unit 731

Image Source From 1937 to 1945, the imperial Japanese Army developed a covert biological and chemical warfare research experiment called Unit 731. Based in the large city of Harbin, Unit 731 was responsible for some of the most atrocious war crimes in history. Chinese and Russian subjects — men, women, children, infants, the elderly, and pregnant women — were subjected to experiments which included the removal of organs from a live body, amputation for the study of blood loss, germ warfare attacks, and weapons testing. Some prisoners even had their stomachs surgically removed and their esophagus reattached to the intestines. Many of the scientists involved in Unit 731 rose to prominent careers in politics, academia, business, and medicine.

2. Radioactive Materials in Pregnant Women

Image Source Shortly after World War II, with the impending Cold War forefront on the minds of Americans, many medical researchers were preoccupied with the idea of radioactivity and chemical warfare. In an experiment at Vanderbilt University, 829 pregnant women were given “vitamin drinks” they were told would improve the health of their unborn babies. Instead, the drinks contained radioactive iron and the researchers were studying how quickly the radioisotope crossed into the placenta. At least seven of the babies later died from cancers and leukemia, and the women themselves experienced rashes, bruises, anemia, loss of hair and tooth, and cancer.

1. Mustard Gas Tested on American Military

Image Source In 1943, the U.S. Navy exposed its own sailors to mustard gas. Officially, the Navy was testing the effectiveness of new clothing and gas masks against the deadly gas that had proven so terrifying in the first World War. The worst of the experiments occurred at the Naval Research Laboratory in Washington. Seventeen and 18-year old boys were approached after eight weeks of boot camp and asked if they wanted to participate in an experiment that would help shorten the war. Only when the boys reached the Research Laboratory were they told the experiment involved mustard gas. The participants, almost all of whom suffered severe external and internal burns, were ignored by the Navy and, in some cases, threatened with the Espionage Act. In 1991, the reports were finally declassified and taken before Congress.

28. Prison Inmates as Test Subjects Henrietta Lacks 26. Project QKHILLTOP 25. Stateville Penitentiary Malaria Study Stateville Penitentiary Malaria Study: Primaquine 24. Emma Eckstein 23. Dr. William Beaumont Dr. William Beaumont 21. Electroshock Therapy on Children 21. Project Artichoke 20. Operation Midnight Climax 19. Study of Humans Accidentally Exposed to Fallout Radiation 18. The Monster Experiment 17. Project MKUltra 16. Experiments on Newborns 15. The Aversion Project 14. Medical Experiments on Prison Inmates 13. Sexual Reassignment 12. Effect of Radiation on Testicles 11. Stanford Prison Experiment 10. Syphilis Experiment in Guatemala 9. Tuskegee Syphilis Study 8. Milgram Experiment 7. Infected Mosquitos in Towns 6. Human Experimentation in the Soviet Union 5. Human Experimentation in North Korea 4. Nazi Human Experimentation 3. Unit 731 2. Radioactive Materials in Pregnant Women 1. Mustard Gas Tested on American Military

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Topic: Human Experimentation

Addressing social justice through the lens of henrietta lacks.

Among the many disruptions of the pandemic, one particular disappointment was the cancellation of the in-person annual meeting of the American Society for Bioethics and Humanities (ASBH), scheduled for Baltimore and set to coincide with the Berman Institute’s 25th Anniversary Celebration and the centennial of Henrietta Lacks’s birth. Yet despite the switch to a virtual format, the Berman Institute was able to host a plenary session that was the talk of the meeting and continues to reverberate.

“Social Justice and Bioethics Through the Lens of the Story of Henrietta Lacks,” was moderated by Jeffrey Kahn and featured Ruth Faden as a panelist. She was joined by Henrietta Lacks’s granddaughter, Jeri Lacks, architect Victor Vines, and Georgetown University Law Center bioethicist Patricia King.

Faden began the session by providing an overview of the Henrietta Lacks story, famed in the context of structural injustice.

“The structural injustice of racism defined in pretty much every way how this story unfolded,” she said. “What is wrong about what happened to the Lacks family engages every core element of human well-being. There were assaults on the social basis of respect, and of self-determination, on attachments, on personal security and on health. Mrs. Lacks and her children were poor Black people in a segregated world in which the most profound injustices of racial oppression were daily features of their lives.”

Faden was followed by Jeri Lacks who expressed the importance of continuing to let the world know about her grandmother’s story.

“Her cells were used to develop the polio vaccine and to treat HIV, and in creating in vitro fertilization. She is a person who continues to give life, and to preserve life,” said Lacks. “No matter what your race, your age, your social circumstances, she continues to improve your life.”

Victor Vines, an architect who was part of the architect team leading programming and planning for the National Museum of African American History and Culture and led the feasibility study for what will be Johns Hopkins University’s Henrietta Lacks Hall, spoke next about addressing racial injustice through architecture and design.

“When we started work on Lacks Hall, we didn’t talk a lot about architecture or design. We talked about what that story is that we want to tell through the building. Meeting with the Lacks family was critically important to that,” Vines said. “We had to understand what they went through and what they care about. The building still has to function and house the Berman Institute, so we had to meet their needs. And we discovered a third client, the East Baltimore community. At the end of the day, this building and university reside within that community, and they will be called to embrace this project – or not.”

King concluded the panel with a riveting and wide-ranging discussion that touched upon intersectionality, segregation, the Tuskegee experiments and participation in clinical trials, COVID, race as a social construct, and the role of consent, all within the framework of Henrietta Lacks’s story.

“Our narratives are important and should be thought of as lessons or homework for institutions,” she said. “They not only document the deep distrust we bring to health encounters but also convey relevant aspects of our lives that should be appreciated.”

As the session ended Kahn noted that perhaps it was fortunate the session had been virtual, so the recording “could be shared with others for posterity. I’m not quite speechless, but maybe close,” he said.

Honoring an Immortal Contribution

Johns Hopkins University President Ronald J. Daniels and Paul B. Rothman, CEO of Johns Hopkins Medicine and dean of the medical faculty of the Johns Hopkins University School of Medicine, along with Berman institute Executive Director Jeffrey Kahn and descendants of Henrietta Lacks, recently announced plans to name a new multidisciplinary building on the Johns Hopkins East Baltimore campus in honor of Henrietta Lacks, who was the source of the HeLa cell line that has been critical to numerous advances in medicine.

Surrounded by descendants of Lacks, Daniels made the announcement at the 9th annual Henrietta Lacks Memorial Lecture in the Turner Auditorium in East Baltimore.

“Through her life and her immortal cells, Henrietta Lacks made an immeasurable impact on science and medicine that has touched countless lives around the world,” Daniels said. “This building will stand as a testament to her transformative impact on scientific discovery and the ethics that must undergird its pursuit. We at Johns Hopkins are profoundly grateful to the Lacks family for their partnership as we continue to learn from Mrs. Lacks’ life and to honor her enduring legacy.”

Henrietta Lacks’ contributions to science were not widely known until the 2010 release of the book The Immortal Life of Henrietta Lacks by Rebecca Skloot, which explored Lacks’ life story, her impact on medical science and important bioethical issues. In 2017, HBO and Harpo Studios released a movie based on the book, with Oprah Winfrey starring as Deborah Lacks, Henrietta Lacks’ daughter.

Several Lacks family members attended today’s event. “It is a proud day for the Lacks family. We have been working with Hopkins for many years now on events and projects that honor our grandmother,” said Jeri Lacks, granddaughter of Henrietta Lacks. “They are all meaningful, but this is the ultimate honor, one befitting of her role in advancing modern medicine.”

The building, which will adjoin the Berman Institute of Bioethics’ current home in Deering Hall will support programs that enhance participation and partnership with members of the community in research that can benefit the community, as well as extend the opportunities to further study and promote research ethics and community engagement in research through an expansion of the Berman Institute and its work.

The story portrayed in The Immortal Life of Henrietta Lacks points to several important bioethical issues, including informed consent, medical records privacy, and communication with tissue donors and research participants.

“The story of Henrietta Lacks has encouraged us all to examine, discuss and wrestle with difficult issues that are at the foundation of the ethics of research, and must inform our relationships with the individuals and communities that are part of that research,” said Jeffrey Kahn, director of the Johns Hopkins University Berman Institute of Bioethics. “As a result, students, faculty and the entire research community at Johns Hopkins and around the world do their work with a greater sensitivity to these critical issues.”

In 2013, Johns Hopkins worked with members of the Lacks family and the National Institutes of Health (NIH) to help broker an agreement that requires scientists to receive permission to use Henrietta Lacks’ genetic blueprint in NIH-funded research.

The NIH committee tasked with overseeing the use of HeLa cells now includes two members of the Lacks family. The medical research community has also made significant strides in improving research practices, in part thanks to the lessons learned from Henrietta Lacks’ story.

“It has been an honor for me to work with the Lacks family on how we can recognize the contribution of Henrietta Lacks to medical research and the community. Their willingness to focus on the positive impact of the HeLa cells has been inspiring to me. The Henrietta Lacks story has led many researchers to rededicate themselves to working more closely with patients,” said Daniel E. Ford, vice dean for clinical investigation in the school of medicine. “The new building will be a hub for the community engagement and collaboration program of the NIH-supported Institute for Clinical and Translational Research.”

Groundbreaking on the building that will be named for Henrietta Lacks is scheduled for 2020 with an anticipated completion in 2022.

To learn more about Henrietta Lacks and the wide-ranging impact of HeLa cells on medical research,

please visit: www.hopkinsmedicine.org/henriettalacks .

Alan Regenberg, MBE

Alan is also engaged in a broad range of research projects and programs, including the Berman Institute’s science programs: the Stem Cell Policy and Ethics (SCOPE) Program ; the Program in Ethics and Brain Sciences (PEBS-Neuroethics) ; and the Hinxton Group , an international consortium on stem cells, ethics and law; and the eSchool+ Initiative . Recent research has focused on using deliberative democracy tools to engage with communities about their values for allocating scarce medical resources like ventilators in disasters like pandemics. Additional recent work has focused on ethical challenges related to gene editing, stem cell research, social media, public engagement, vaccines, and neuroethics. ( Publications )

Joseph Ali, JD

Vaccinating pregnant women against ebola.

In a STAT News opinion piece, Johns Hopkins University experts, including our Ruth Faden, argued it is unfair  to deny pregnant and lactating women the experimental Ebola vaccine if they wish to take it, given the great risk the virus poses to those who are exposed to it.

“From a public health perspective and an ethical perspective, the decision to exclude pregnant and lactating women is utterly indefensible,” they wrote.

The authors are members of Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group, which has brought together an international team of experts in bioethics, maternal immunization, maternal-fetal medicine, obstetrics, pediatrics, philosophy, public health, and vaccine research to provide specific recommendations developed to address this critical gap in vaccine research and development and epidemic response. This group recognizes that excluding pregnant women from efforts to develop and deploy vaccines against emerging threats is not acceptable.

Nancy E. Kass, ScD

Dr. Kass is coeditor (with Ruth Faden) of HIV, AIDS and Childbearing: Public Policy, Private Lives (Oxford University Press, 1996).

She has served as consultant to the President’s Advisory Committee on Human Radiation Experiments, to the National Bioethics Advisory Commission, and to the National Academy of Sciences. Dr. Kass currently serves as the Chair of the NIH Precision Medicine Initiative Central IRB; she previously co-chaired the National Cancer Institute (NCI) Committee to develop Recommendations for Informed Consent Documents for Cancer Clinical Trials and served on the NCI’s central IRB. Current research projects examine improving informed consent in human research, ethical guidance development for Ebola and other infectious outbreaks, and ethics and learning health care. Dr. Kass teaches the Bloomberg School of Public Health’s course on U.S. and International Research Ethics and Integrity, she served as the director of the School’s PhD program in bioethics and health policy from its inception until 2016, and she has directed (with Adnan Hyder) the Johns Hopkins Fogarty African Bioethics Training Program since its inception in 2000. Dr. Kass is an elected member of the Institute of Medicine (now National Academy of Medicine) and an elected Fellow of the Hastings Center.

Jeremy Sugarman, MD, MPH, MA

He was the founding director of the Trent Center for Bioethics, Humanities and History of Medicine at Duke University where he was also a professor of medicine and philosophy. He was appointed as an Academic Icon at the University of Malaya and is a faculty affiliate of the Kennedy Institute of Ethics at Georgetown University.

Dr. Sugarman was the longstanding chair of the Ethics Working Group of the HIV Prevention Trials Network. He is currently a member of the Scientific and Research Advisory Board for the Canadian Blood Service and the Ethics and Public Policy Committees of the International Society for Stem Cell Research. He co-leads the Ethics and Regulatory Core of the NIH Health Care Systems Research Collaboratory and is co-chair of the Johns Hopkins’ Institutional Stem Cell Research Oversight Committee.

Dr. Sugarman has been elected as a member of the American Society of Clinical Investigation, Association of American Physicians, and the National Academy of Medicine (formerly the Institute of Medicine). He is a fellow of the American Association for the Advancement of Science, the American College of Physicians and the Hastings Center. He also received a Doctor of Science, honoris causa, from New York Medical College.

Ugly past of U.S. human experiments uncovered

Shocking as it may seem, U.S. government doctors once thought it was fine to experiment on disabled people and prison inmates. Such experiments included giving hepatitis to mental patients in Connecticut, squirting a pandemic flu virus up the noses of prisoners in Maryland, and injecting cancer cells into chronically ill people at a New York hospital.

Much of this horrific history is 40 to 80 years old, but it is the backdrop for a meeting in Washington this week by a presidential bioethics commission. The meeting was triggered by the government's apology last fall for federal doctors infecting prisoners and mental patients in Guatemala with syphilis 65 years ago.

U.S. officials also acknowledged there had been dozens of similar experiments in the United States — studies that often involved making healthy people sick.

An exhaustive review by The Associated Press of medical journal reports and decades-old press clippings found more than 40 such studies. At best, these were a search for lifesaving treatments; at worst, some amounted to curiosity-satisfying experiments that hurt people but provided no useful results.

Inevitably, they will be compared to the well-known Tuskegee syphilis study. In that episode, U.S. health officials tracked 600 black men in Alabama who already had syphilis but didn't give them adequate treatment even after penicillin became available.

These studies were worse in at least one respect — they violated the concept of "first do no harm," a fundamental medical principle that stretches back centuries.

"When you give somebody a disease — even by the standards of their time — you really cross the key ethical norm of the profession," said Arthur Caplan, director of the University of Pennsylvania's Center for Bioethics.

Attitude similar to Nazi experiments Some of these studies, mostly from the 1940s to the '60s, apparently were never covered by news media. Others were reported at the time, but the focus was on the promise of enduring new cures, while glossing over how test subjects were treated.

Attitudes about medical research were different then. Infectious diseases killed many more people years ago, and doctors worked urgently to invent and test cures. Many prominent researchers felt it was legitimate to experiment on people who did not have full rights in society — people like prisoners, mental patients, poor blacks. It was an attitude in some ways similar to that of Nazi doctors experimenting on Jews.

"There was definitely a sense — that we don't have today — that sacrifice for the nation was important," said Laura Stark, a Wesleyan University assistant professor of science in society, who is writing a book about past federal medical experiments.

The AP review of past research found:

• A federally funded study begun in 1942 injected experimental flu vaccine in male patients at a state insane asylum in Ypsilanti, Mich., then exposed them to flu several months later. It was co-authored by Dr. Jonas Salk, who a decade later would become famous as inventor of the polio vaccine.

Some of the men weren't able to describe their symptoms, raising serious questions about how well they understood what was being done to them. One newspaper account mentioned the test subjects were "senile and debilitated." Then it quickly moved on to the promising results.

• In federally funded studies in the 1940s, noted researcher Dr. W. Paul Havens Jr. exposed men to hepatitis in a series of experiments, including one using patients from mental institutions in Middletown and Norwich, Conn. Havens, a World Health Organization expert on viral diseases, was one of the first scientists to differentiate types of hepatitis and their causes.

A search of various news archives found no mention of the mental patients study, which made eight healthy men ill but broke no new ground in understanding the disease.

• Researchers in the mid-1940s studied the transmission of a deadly stomach bug by having young men swallow unfiltered stool suspension. The study was conducted at the New York State Vocational Institution, a reformatory prison in West Coxsackie. The point was to see how well the disease spread that way as compared to spraying the germs and having test subjects breathe it. Swallowing it was a more effective way to spread the disease, the researchers concluded. The study doesn't explain if the men were rewarded for this awful task.
• A University of Minnesota study in the late 1940s injected 11 public service employee volunteers with malaria, then starved them for five days. Some were also subjected to hard labor, and those men lost an average of 14 pounds. They were treated for malarial fevers with quinine sulfate. One of the authors was Ancel Keys, a noted dietary scientist who developed K-rations for the military and the Mediterranean diet for the public. But a search of various news archives found no mention of the study.
• For a study in 1957, when the Asian flu pandemic was spreading, federal researchers sprayed the virus in the noses of 23 inmates at Patuxent prison in Jessup, Md., to compare their reactions to those of 32 virus-exposed inmates who had been given a new vaccine.
• Government researchers in the 1950s tried to infect about two dozen volunteering prison inmates with gonorrhea using two different methods in an experiment at a federal penitentiary in Atlanta. The bacteria was pumped directly into the urinary tract through the penis, according to their paper.

The men quickly developed the disease, but the researchers noted this method wasn't comparable to how men normally got infected — by having sex with an infected partner. The men were later treated with antibiotics. The study was published in the Journal of the American Medical Association, but there was no mention of it in various news archives.

Though people in the studies were usually described as volunteers, historians and ethicists have questioned how well these people understood what was to be done to them and why, or whether they were coerced.

Victims for science Prisoners have long been victimized for the sake of science. In 1915, the U.S. government's Dr. Joseph Goldberger — today remembered as a public health hero — recruited Mississippi inmates to go on special rations to prove his theory that the painful illness pellagra was caused by a dietary deficiency. (The men were offered pardons for their participation.)

But studies using prisoners were uncommon in the first few decades of the 20th century, and usually performed by researchers considered eccentric even by the standards of the day. One was Dr. L.L. Stanley, resident physician at San Quentin prison in California, who around 1920 attempted to treat older, "devitalized men" by implanting in them testicles from livestock and from recently executed convicts.

Newspapers wrote about Stanley's experiments, but the lack of outrage is striking.

"Enter San Quentin penitentiary in the role of the Fountain of Youth — an institution where the years are made to roll back for men of failing mentality and vitality and where the spring is restored to the step, wit to the brain, vigor to the muscles and ambition to the spirit. All this has been done, is being done ... by a surgeon with a scalpel," began one rosy report published in November 1919 in The Washington Post.

Around the time of World War II, prisoners were enlisted to help the war effort by taking part in studies that could help the troops. For example, a series of malaria studies at Stateville Penitentiary in Illinois and two other prisons was designed to test antimalarial drugs that could help soldiers fighting in the Pacific.

It was at about this time that prosecution of Nazi doctors in 1947 led to the "Nuremberg Code," a set of international rules to protect human test subjects. Many U.S. doctors essentially ignored them, arguing that they applied to Nazi atrocities — not to American medicine.

The late 1940s and 1950s saw huge growth in the U.S. pharmaceutical and health care industries, accompanied by a boom in prisoner experiments funded by both the government and corporations. By the 1960s, at least half the states allowed prisoners to be used as medical guinea pigs.

But two studies in the 1960s proved to be turning points in the public's attitude toward the way test subjects were treated.

The first came to light in 1963. Researchers injected cancer cells into 19 old and debilitated patients at a Jewish Chronic Disease Hospital in the New York borough of Brooklyn to see if their bodies would reject them.

The hospital director said the patients were not told they were being injected with cancer cells because there was no need — the cells were deemed harmless. But the experiment upset a lawyer named William Hyman who sat on the hospital's board of directors. The state investigated, and the hospital ultimately said any such experiments would require the patient's written consent.

At nearby Staten Island, from 1963 to 1966, a controversial medical study was conducted at the Willowbrook State School for children with mental retardation. The children were intentionally given hepatitis orally and by injection to see if they could then be cured with gamma globulin.

Those two studies — along with the Tuskegee experiment revealed in 1972 — proved to be a "holy trinity" that sparked extensive and critical media coverage and public disgust, said Susan Reverby, the Wellesley College historian who first discovered records of the syphilis study in Guatemala.

'My back is on fire!' By the early 1970s, even experiments involving prisoners were considered scandalous. In widely covered congressional hearings in 1973, pharmaceutical industry officials acknowledged they were using prisoners for testing because they were cheaper than chimpanzees.

Holmesburg Prison in Philadelphia made extensive use of inmates for medical experiments. Some of the victims are still around to talk about it. Edward "Yusef" Anthony, featured in a book about the studies, says he agreed to have a layer of skin peeled off his back, which was coated with searing chemicals to test a drug. He did that for money to buy cigarettes in prison.

"I said 'Oh my God, my back is on fire! Take this ... off me!'" Anthony said in an interview with The Associated Press, as he recalled the beginning of weeks of intense itching and agonizing pain.

The government responded with reforms. Among them: The U.S. Bureau of Prisons in the mid-1970s effectively excluded all research by drug companies and other outside agencies within federal prisons.

As the supply of prisoners and mental patients dried up, researchers looked to other countries.

It made sense. Clinical trials could be done more cheaply and with fewer rules. And it was easy to find patients who were taking no medication, a factor that can complicate tests of other drugs.

Additional sets of ethical guidelines have been enacted, and few believe that another Guatemala study could happen today. "It's not that we're out infecting anybody with things," Caplan said.

Still, in the last 15 years, two international studies sparked outrage.

One was likened to Tuskegee. U.S.-funded doctors failed to give the AIDS drug AZT to all the HIV-infected pregnant women in a study in Uganda even though it would have protected their newborns. U.S. health officials argued the study would answer questions about AZT's use in the developing world.

The other study, by Pfizer Inc., gave an antibiotic named Trovan to children with meningitis in Nigeria, although there were doubts about its effectiveness for that disease. Critics blamed the experiment for the deaths of 11 children and the disabling of scores of others. Pfizer settled a lawsuit with Nigerian officials for $75 million but admitted no wrongdoing.

Last year, the U.S. Department of Health and Human Services' inspector general reported that between 40 and 65 percent of clinical studies of federally regulated medical products were done in other countries in 2008, and that proportion probably has grown. The report also noted that U.S. regulators inspected fewer than 1 percent of foreign clinical trial sites.

Monitoring research is complicated, and rules that are too rigid could slow new drug development. But it's often hard to get information on international trials, sometimes because of missing records and a paucity of audits, said Dr. Kevin Schulman, a Duke University professor of medicine who has written on the ethics of international studies.

Syphilis study These issues were still being debated when, last October, the Guatemala study came to light.

In the 1946-48 study, American scientists infected prisoners and patients in a mental hospital in Guatemala with syphilis, apparently to test whether penicillin could prevent some sexually transmitted disease. The study came up with no useful information and was hidden for decades.

Story: U.S. apologizes for Guatemala syphilis experiments

The Guatemala study nauseated ethicists on multiple levels. Beyond infecting patients with a terrible illness, it was clear that people in the study did not understand what was being done to them or were not able to give their consent. Indeed, though it happened at a time when scientists were quick to publish research that showed frank disinterest in the rights of study participants, this study was buried in file drawers.

"It was unusually unethical, even at the time," said Stark, the Wesleyan researcher.

"When the president was briefed on the details of the Guatemalan episode, one of his first questions was whether this sort of thing could still happen today," said Rick Weiss, a spokesman for the White House Office of Science and Technology Policy.

That it occurred overseas was an opening for the Obama administration to have the bioethics panel seek a new evaluation of international medical studies. The president also asked the Institute of Medicine to further probe the Guatemala study, but the IOM relinquished the assignment in November, after reporting its own conflict of interest: In the 1940s, five members of one of the IOM's sister organizations played prominent roles in federal syphilis research and had links to the Guatemala study.

So the bioethics commission gets both tasks. To focus on federally funded international studies, the commission has formed an international panel of about a dozen experts in ethics, science and clinical research. Regarding the look at the Guatemala study, the commission has hired 15 staff investigators and is working with additional historians and other consulting experts.

The panel is to send a report to Obama by September. Any further steps would be up to the administration.

Some experts say that given such a tight deadline, it would be a surprise if the commission produced substantive new information about past studies. "They face a really tough challenge," Caplan said.

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• 25 April 2018

The ethics of experimenting with human brain tissue

• Nita A. Farahany 0 ,
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• Steven Hyman 2 ,
• Christof Koch 3 ,
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• Sergiu P. Pașca 5 ,
• Nenad Sestan 6 ,
• Paola Arlotta 7 ,
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• Jonathan Ting 9 ,
• Jeantine E. Lunshof 10 ,
• Eswar P. R. Iyer 11 ,
• Insoo Hyun 12 ,
• Beatrice H. Capestany 13 ,
• George M. Church 14 ,
• Hao Huang 15 &
• Hongjun Song 16

Nita A. Farahany is professor of law and philosophy at Duke University, director of the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA.

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Henry T. Greely is professor of law, director of the Center for Law and the Biosciences, and director of the Stanford Program in Neuroscience and Society at Stanford University, California, USA.

Steven Hyman is director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard University; and Harvard University distinguished service professor in the Department of Stem Cell and Regenerative Biology at Harvard University, Cambridge, Massachusetts, USA.

Christof Koch is the chief scientist and president at the Allen Institute for Brain Science, Seattle, Washington, USA.

Christine Grady is chief of the Department of Bioethics at the National Institutes of Health Clinical Center, Bethesda, Maryland, USA.

Sergiu P. Pașca is assistant professor of psychiatry and behavioural sciences at Stanford University, Palo Alto, California, USA.

Nenad Sestan is professor of neuroscience, of genetics, of psychiatry, and of comparative medicine at the Yale School of Medicine, New Haven, Connecticut, USA.

Paola Arlotta is professor of stem cell and regenerative biology at Harvard University, Cambridge, Massachusetts, USA.

James L. Bernat is professor of neurology and medicine (active emeritus) at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, USA.

Jonathan Ting is assistant investigator at the Allen Institute for Brain Science, Seattle, Washington, USA.

Jeantine E. Lunshof is research scientist-ethicist at MIT Media Lab in Cambridge, Massachusetts; ethics consultant to the Department of Genetics at Harvard Medical School, Boston, Massachusetts, USA; assistant professor in the Department of Genetics, University of Groningen, Groningen, the Netherlands.

Eswar P. R. Iyer is a postdoctoral fellow at Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Insoo Hyun is associate professor of bioethics and philosophy at Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Beatrice H. Capestany is a postdoctoral fellow at the Science, Law, and Policy Lab at the Duke Initiative for Science & Society, Duke University, Durham, North Carolina, USA.

George M. Church is professor of genetics at Department of Genetics, Harvard Medical School, and Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA.

Hao Huang is associate professor of radiology at University of Pennsylvania, Philadelphia, USA.

Hongjun Song is Perelman professor of neuroscience at University of Pennsylvania in Philadelphia, USA.

If researchers could create brain tissue in the laboratory that might appear to have conscious experiences or subjective phenomenal states, would that tissue deserve any of the protections routinely given to human or animal research subjects?

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Classic Psychology Experiments

The history of psychology is filled with fascinating studies and classic psychology experiments that helped change the way we think about ourselves and human behavior. Sometimes the results of these experiments were so surprising they challenged conventional wisdom about the human mind and actions. In other cases, these experiments were also quite controversial.

Some of the most famous examples include Milgram's obedience experiment and Zimbardo's prison experiment. Explore some of these classic psychology experiments to learn more about some of the best-known research in psychology history.

Harlow’s Rhesus Monkey Experiments

In a series of controversial experiments conducted in the late 1950s and early 1960s, psychologist Harry Harlow demonstrated the powerful effects of love on normal development. By showing the devastating effects of deprivation on young rhesus monkeys , Harlow revealed the importance of love for healthy childhood development.

His experiments were often unethical and shockingly cruel, yet they uncovered fundamental truths that have heavily influenced our understanding of child development.

In one famous version of the experiments, infant monkeys were separated from their mothers immediately after birth and placed in an environment where they had access to either a wire monkey "mother" or a version of the faux-mother covered in a soft-terry cloth. While the wire mother provided food, the cloth mother provided only softness and comfort.

Harlow found that while the infant monkeys would go to the wire mother for food, they vastly preferred the company of the soft and comforting cloth mother. The study demonstrated that maternal bonds   were about much more than simply providing nourishment and that comfort and security played a major role in the formation of attachments .

Pavlov’s Classical Conditioning Experiments

The concept of classical conditioning is studied by every entry-level psychology student, so it may be surprising to learn that the man who first noted this phenomenon was not a psychologist at all. Pavlov was actually studying the digestive systems of dogs when he noticed that his subjects began to salivate whenever they saw his lab assistant.

What he soon discovered through his experiments was that certain responses (drooling) could be conditioned by associating a previously neutral stimulus (metronome or buzzer) with a stimulus that naturally and automatically triggers a response (food). Pavlov's experiments with dogs established classical conditioning.

The Asch Conformity Experiments

Researchers have long been interested in the degree to which people follow or rebel against social norms. During the 1950s, psychologist Solomon Asch conducted a series of experiments designed to demonstrate the powers of conformity in groups.  

The study revealed that people are surprisingly susceptible to going along with the group, even when they know the group is wrong.​ In Asch's studies, students were told that they were taking a vision test and were asked to identify which of three lines was the same length as a target line.

When asked alone, the students were highly accurate in their assessments. In other trials, confederate participants intentionally picked the incorrect line. As a result, many of the real participants gave the same answer as the other students, demonstrating how conformity could be both a powerful and subtle influence on human behavior.

Skinner's Operant Conditioning Experiments

Skinner studied how behavior can be reinforced to be repeated or weakened to be extinguished. He designed the Skinner Box where an animal, often a rodent, would be given a food pellet or an electric shock. A rat would learn that pressing a level delivered a food pellet. Or the rat would learn to press the lever in order to halt electric shocks.

Then, the animal may learn to associate a light or sound with being able to get the reward or halt negative stimuli by pressing the lever. Furthermore, he studied whether continuous, fixed ratio, fixed interval , variable ratio, and variable interval reinforcement led to faster response or learning.

Milgram’s Obedience Experiments

In Milgram's experiment , participants were asked to deliver electrical shocks to a "learner" whenever an incorrect answer was given. In reality, the learner was actually a confederate in the experiment who pretended to be shocked. The purpose of the experiment was to determine how far people were willing to go in order to obey the commands of an authority figure.

Milgram  found that 65% of participants were willing to deliver the maximum level of shocks   despite the fact that the learner seemed to be in serious distress or even unconscious.

Why This Experiment Is Notable

Milgram's experiment is one of the most controversial in psychology history. Many participants experienced considerable distress as a result of their participation and in many cases were never debriefed after the conclusion of the experiment. The experiment played a role in the development of ethical guidelines for the use of human participants in psychology experiments.

The Stanford Prison Experiment

Philip Zimbardo's famous experiment cast regular students in the roles of prisoners and prison guards. While the study was originally slated to last 2 weeks, it had to be halted after just 6 days because the guards became abusive and the prisoners began to show signs of extreme stress and anxiety.

Zimbardo's famous study was referred to after the abuses in Abu Ghraib came to light. Many experts believe that such group behaviors are heavily influenced by the power of the situation and the behavioral expectations placed on people cast in different roles.

It is worth noting criticisms of Zimbardo's experiment, however. While the general recollection of the experiment is that the guards became excessively abusive on their own as a natural response to their role, the reality is that they were explicitly instructed to mistreat the prisoners, potentially detracting from the conclusions of the study.

Van rosmalen L, Van der veer R, Van der horst FCP. The nature of love: Harlow, Bowlby and Bettelheim on affectionless mothers. Hist Psychiatry. 2020. doi:10.1177/0957154X19898997

Gantt WH . Ivan Pavlov . Encyclopaedia Brittanica .

Jeon, HL. The environmental factor within the Solomon Asch Line Test . International Journal of Social Science and Humanity. 2014;4(4):264-268. doi:10.7763/IJSSH.2014.V4.360 

Koren M. B.F. Skinner: The man who taught pigeons to play ping-pong and rats to pull levers . Smithsonian Magazine .

B.F. Skinner Foundation. A brief survey of operant behavior .

Gonzalez-franco M, Slater M, Birney ME, Swapp D, Haslam SA, Reicher SD. Participant concerns for the Learner in a Virtual Reality replication of the Milgram obedience study. PLoS ONE. 2018;13(12):e0209704. doi:10.1371/journal.pone.0209704

Zimbardo PG. Philip G. Zimbardo on his career and the Stanford Prison Experiment's 40th anniversary. Interview by Scott Drury, Scott A. Hutchens, Duane E. Shuttlesworth, and Carole L. White. Hist Psychol. 2012;15(2):161-170. doi:10.1037/a0025884

Le texier T. Debunking the Stanford Prison Experiment. Am Psychol. 2019;74(7):823-839. doi:10.1037/amp0000401

Perry G. Deception and illusion in Milgram's accounts of the Obedience Experiments . Theoretical & Applied Ethics . 2013;2(2):79-92.

Specter M. Drool: How Everyone Gets Pavlov Wrong . The New Yorker. 2014; November 24.

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Human Experimentation List (in Psychology)

Although experimentations on human subjects often prove to be ethically questionable, they have been carried out for almost two centuries and are now under strictly controlled and regulated by law.

What Is Human Experimentation?

Human experimentation is a systematic, scientific investigation where human beings serve as subjects in either medical (clinical) or non-medical research. Human subject research can be interventional or observational. This research method led to many revolutionary advances ever since its first use at the end of the 18th century. 

Observational vs Interventional Research

In an observational research, investigators record their observations and analyze data without administering an intervention. Observational studies focus on aspects such as risk factors, disease progression, and disease treatments. Human subject research in the social sciences, for example, may involve surveys, questionnaires, interviews, and focus groups.

On the other hand, in an interventional research, investigators manipulate the subjects or their environment in order to modify specific processes or results. The most common human intervention studies are clinical trials in which new drugs and vaccines are being evaluated.

Examples of Human Experimentation

Human experiments were used extensively throughout the twentieth century. They were subject to both fame, controversy, and rage. Let’s have a look at some of the best-known experiments performed on humans.

The smallpox experiment

The earliest known human experimentation was done in 1796 by English physician Edward Jenner, famous for developing the world’s first vaccine.

As a country doctor, Jenner was aware of the fact that milkmaids rarely caught smallpox. However, since they were in frequent contact with cows, they often contracted cowpox. Jenner speculated that cowpox produced immunity against smallpox. To prove this theory, he injected fluid from a cowpox infection into the skin of his gardener’s son, eight-year-old James Phipps. When several weeks later Jenner exposed the boy to smallpox, he found that James has indeed become immune to the disease.

Following Jenner’s model, scientists in the 19th and 20th centuries developed new vaccines to fight many deadly diseases including polio, measles, and tetanus.

The Tuskegee experiment

In 1932, scientists at the Tuskegee Institute in Alabama started studying the natural progression of syphilis, a disease that represented a major health problem at the time. Six hundred black men were enrolled in the project that lasted for four decades; two-third of them had the disease.

The subjects of the study, officially known as the Tuskegee Study of Untreated Syphilis in the Negro Male, were not informed about the research. Instead, they were led to believe that they were receiving treatment for "bad blood"—a term that was used to describe several serious illnesses at the time—and promised free medical care and burial insurance as an incentive.

The men were given only placebos such as aspirin and mineral supplements. They were not treated for syphilis, although penicillin became an effective cure for the disease in 1947. As a result, many participants died from complications of syphilis. The survivors were given treatment in 1972, after the nature of the study became publicly known.

Henrietta Lacks

Henrietta Lacks was a poor and uneducated African American tobacco farmer from Baltimore, Maryland with cervical cancer. In 1951, scientists at Baltimore’s Johns Hopkins Hospital collected cells from her tissue sample without her knowledge.

Henrietta’s cells, nicknamed HeLa cells, soon became invaluable in medical research. These were the first cells to be successfully kept alive and cloned. They were essential in developing the polio vaccine and were sent to space in the first space missions to see how they would be affected by zero gravity. HeLa cells were also used in gene mapping, in vitro fertilization, and countless other scientific endeavors.

The Milgram experiment

In 1961, Yale University psychologist Stanley Milgram carried out what has become one of the best-known studies of obedience in psychology. Milgram conducted a series of experiments to determine to what extent people are willing to obey instructions that involve harming others.

Participants in Milgram’s experiment were asked to be "teachers" to a group of people placed in a separate room. They were instructed to administer an electric shock to “learners” every time they answer a question incorrectly. With every new incorrect answer, they were to increase the intensity of the electric shock, without realizing that the shocks were not real.

Despite Milgram’s expectations that no one would accept administering strong electric shocks to the learners, to his surprise, 65% of participants obeyed the instructions until the very end of the experiment, going all the way up to 450 volts.

The Bystander Effect

When 28-year-old Kitty Genovese was killed outside her apartment in New York City in 1964, it was reported that none of her neighbors stepped in to assist or call the police. A few years later, social psychologists Bibb Latane and John Darley decided to do a series of experiments to demonstrate this psychological phenomenon known as the bystander effect.

The participants in Latane and Darley’s experiment were confronted with several types of emergencies, like witnessing a seizure or smoke entering through air vents. The psychologists found that the larger the number of witnesses or “bystanders”, the more time it took for people to respond to the emergency. The experiment showed the diffusion of responsibility, that is, when surrounded by others, people expect someone else to take action. The lack of action was also a result of the social influence effect where individuals observe the behavior of those around them before deciding how to act.

The Stanford Prison Experiment

Psychologist Philip Zimbardo was the author of the infamous 1971 social psychology experiment that investigated the psychological effects of perceived power. Zimbardo was interested in finding out whether the brutality reported among guards in American prisons was due to their personality traits or was mostly situational and had to do with the prison environment.

Zimbardo converted a basement of the Stanford University psychology department into a “prison” and recruited volunteers to take part in a study of the psychological effects of prison life. Prisoners were arrested at their homes without warning and taken to the local police station, after which they were blindfolded and put in prison. Guards were instructed to do whatever was necessary to maintain law and order among prisoners except for resorting to physical violence.

The Stanford prison experiment revealed that people readily conformed to the stereotypical social roles they were expected to play. When they were placed in a position of authority, prison guards began to act in ways they would not usually behave.

Growth hormone therapy

The human growth hormone (hGH) was originally made available in the late 1950s to treat hormone-deficient children who would otherwise remain extremely short. Until the 1980s, only children lacking the hGH were eligible to receive the treatment.

With the rise of genetic engineering, however, the hormone has become more readily available. At the National Institutes of Health (NIH), the growth hormone has been administered also to perfectly healthy children who are short for their age, in spite of the fact that the procedure poses significant physical and psychological risks.

Ethics of Human Experimentation

There is no doubt that research involving human subjects is indispensable and has led to an improvement in the quality of lives and numerous medical breakthroughs. At the same time, as the above examples show, human experimentation has often been on the limit of what is ethically acceptable.

When Is Human Experimentation Criminal?

Jenner’s vaccine experiment was fortunately successful, but exposing a child to a deadly disease in the name of medical research is today considered as unethical. The HeLa cells and Tuskegee experiments have been cited as examples of racial discrimination in science. The Stanford study has been heavily criticized as unethical due to its lack of fully informed consent by prisoners to whom the arrests came as a surprise. The NIH treatment of short children is often seen as a profitable pharmacologic solution to what is fundamentally a social problem.

In addition, in order to ensure sufficient participation in research, human experimentation was frequently done among the most vulnerable population groups such as prisoners, poor people, minorities, mental patients, and children. Bill Clinton, for example, apologized to the communities affected by the Tuskegee experiments.

So how can researchers achieve a balance and justify exposing individual human subjects to risk for the sake of the advancement of science?

Ethical guidelines for human research

Ethical guidelines for regulating the use of human subjects in research were developed in response to numerous unethical experiments carried out throughout the 20th century. In the past sixty years, there has been a rapid emergence of various codes, regulations, and acts to govern ethical research in humans. In addition, several organizations were put in place to help monitor human experimentations.

The Nuremberg Code

The Nuremberg Code is a set of international rules and research ethics principles that were created to protect human test subjects. The code was established in 1947 as a result of the Nuremberg trials at the end of the Second World War. Originally, the code aimed to protect human subjects from any cruelty and exploitation similar to what the prisoners endured during the war.

The Nuremberg Code states that the voluntary consent in research is essential and that participants have the right to ask to end treatment at any moment. Furthermore, treatments can be carried only by licensed professionals who must terminate their study if the subjects are in danger.

The Nuremberg Code remains the most important document in the history of the ethics of medical research. It serves as a blueprint for today's principles that ensure the rights of subjects in human experimentation.

The Belmont report

The Belmont Report was established in 1978 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The report describes the ethical behaviors in research that involve human subjects. It includes three ethical principles that must be taken into account when using human subjects for research:

• Respect for persons: individuals should be treated as autonomous agents and people with diminished autonomy are entitled to protection
• Beneficence: maximizing benefits and minimizing possible harms in human experimentation, that is, acting in the best interest of the participant
• Justice: informed consent, assessment of risks and benefits, fair treatment, and unbiased selection of subjects.

The Belmont Report provides the moral framework for understanding regulations on the use of humans in experimental methods in the United States.

Food and Drug Administration regulations

The Food and Drug Administration (FDA) is the highest authority of human subjects protection in research in the United States. The FDA regulations for the conduct of clinical trials have been in effect since the 1970s. These regulations require informing participants in an experiment that they could be used as control subjects or given a placebo, and that in certain cases alternative therapies may exist, and obtaining their written consent.

Ethics committees

To protect the rights and well-being of research participants, and at the same time allow obtaining meaningful results and insights into human behavior, all current biomedical and psychological research must go through a strict ethical review process.

Ethics committees assess and review trial designs. They approve, review, and monitor all research involving humans. Their task is to verify that subjects are not exposed to any unnecessary risks according to the key ethical guidelines including the assurance of confidentiality, informed consent, and debriefing.

Ethics committees in the European Union are bodies responsible for oversight of medical or human research studies in EU member states.

Institutional review boards

In the United States, ethics committees are usually known as institutional review boards. Institutional review boards (IRB), also called ethical review boards, are independent ethics committees that review Health and Human Services research proposals involving human subjects. The aim of the institutional review board is to ensure that the proposals meet the ethical foundations of the regulations.

Any study conducted by a university or research organization has to be approved by an institutional review board, often even before investigators can apply for funding. This is the case for any research in anthropology, economics, political science, and sociology as it is for clinical or experimental research in medicine and psychology.

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• The Psychology of Long Distance Relationships
• Operant Conditioning (Examples + Research)
• Beck’s Depression Inventory (BDI Test)
• Variable Interval Reinforcement Schedule (Examples)
• Concrete Operational Stage (3rd Cognitive Development)

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Science News

How pieces of live human brain are helping scientists map nerve cells.

An audacious project aims to figure out how humans are different from other creatures

MENAGERIE OF NEURONS  Studies of live human brain tissue have revealed cells like this reconstructed pyramidal nerve cell in exquisite detail.

Allen Institute

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By Laura Sanders

August 7, 2019 at 6:00 am

The golf ball–sized chunk of brain is not cooperating. It’s thicker than usual, and bloodier. One side has a swath of tissue that looks, to my untrained eye, like gristle.

Nick Dee, the neuroscientist charged with quickly cutting the chunk into neat pieces, confers with his colleagues. “We can trim off that ugliness on the side,” he says. The “ugliness” is the brain’s connective tissue called white matter.

To produce useful slices for experiments, the brain tissue must be trimmed, superglued to a lipstick-sized base and then fed into a lab version of a deli slicer. But this difficult chunk isn’t cutting nicely. Dee and colleagues pull it off the base, trim it again and reglue.

Half an hour earlier, this piece of neural tissue was tucked inside a 41-year-old woman’s head, on her left side, just above the ear. Surgeons removed the tissue to reach a deeper part of her brain thought to be causing severe seizures. Privacy rules prevent me from knowing much about her; I don’t know her name, much less her first memory, favorite meal or sense of humor. But within this piece of tissue, which the patient generously donated, are clues to how her brain — all of our brains, really — create the mind.

Dee’s team is working fast because this piece of brain is alive. Some of the cells can still behave as if they are a part of a person’s brain, which means they hold enormous potential for scientists who want to understand how we remember, plan, behave and feel. After Dee and his team do their part, pieces of the woman’s brain will be whisked into the hands of eager scientists, where the cells will be photographed, zapped with electricity, relieved of their genetic material and even infected with viruses that make them glow green and red.

It’s all part of a project at the Seattle-based Allen Institute for Brain Science, funded largely by private money plus some U.S. government grants. Now in its sixth year, the project relies on a network of scientists, neurosurgeons and patients who are willing to donate brain tissue removed during surgery. The ultimate aim is to answer one of the biggest questions in neuroscience: What makes us human?

The answer won’t be simple. But already, the project has turned up hints about what makes the human brain so powerful. Live-tissue experiments have revealed cellular quirks that may be specific to primates and have turned up new details about a mysterious type of nerve cell, or neuron. Other tantalizing discoveries show that humans and mice have very similar numbers of neuron types. This kind of detailed cellular reckoning is a necessary early step on the path to understanding human thoughts, behaviors and abilities.

 “We want a complete description of all the types of neurons,” says Christof Koch, chief scientist and president of the Allen Institute for Brain Science. Steady progress over the last six years shows that answers are within reach. Once order is given to the tangle of neurons that populate our brains, scientists can turn their sights to the bigger mysteries, like how those cells create our memories, emotions and even consciousness itself.

On the morning of May 14, I waited outside of a basement operating room at the University of Washington’s Harborview Medical Center. Inside, a neurosurgeon was cutting deep into the woman’s brain. At 10:15, the wide swinging doors opened, and a doctor carried out a clear plastic jar with an orange cap.

Settled at the bottom of the liquid inside was a bit of brain, gently sloshing around with the motion. Tissue-procurement team member Tamara Casper was ready with a cart that carried a blue cooler (the same kind I have in my garage) on the top and two gas canisters below. The piece of brain had tinged the clear solution pink.

It was a colorful reminder that this tissue had, minutes earlier, been inside a skull, where it was helping to create a woman’s mind.

Scientists have other methods to mimic human brains: Brain organoids , small balls of neural tissue that are grown from stem cells ( SN: 3/3/18, p. 22 ), and animals raised in labs have been immensely helpful to neuroscientists. “There’s real value there,” says Allen Institute neurobiologist Ed Lein. “But what they’re not good for is studying the specifics of the final product in the mature brain.”

This particular sample submerged in the pink liquid had spent 41 years piloting a woman’s life. “It’s hard to emphasize how different this is,” Lein says of the project. Other laboratories have studied live tissue removed from human brains, but none have scaled up and systematized the process as much as this group in Seattle. 

“To me, it’s almost mind-blowing that we can study the human brain outside of the human brain,” says Ryder Gwinn, a neurosurgeon at Swedish Medical Center in Seattle who collaborates with Allen Institute scientists.

Gwinn treats people with epilepsy. Medication doesn’t always stop his patients’ seizures. In severe cases, surgery can be a patient’s best bet. In some of these operations, a surgeon cuts away healthy brain tissue to reach the spot deeper in the brain where seizures first spark. Surgeons peel away the skin and remove a cookie-shaped piece of skull, exposing the temporal lobe of the brain, a stretch of the outermost layer called the cortex. Often, a large piece of the temporal lobe comes out, Gwinn says. Some of that neural tissue goes to pathologists. The rest is typically tossed as medical waste — unless Allen Institute scientists can get their hands on it.

“The tissue is terribly scarce,” Koch says. Early on, colleagues, including many Allen Institute researchers, were skeptical that enough samples could be found and brought to the lab in good shape. But after about 140 surgeries, more than 30 this year alone, it’s clear that these brain samples survive the journey beautifully.

As soon as the sample came out of the OR, Casper hooked up the oxygen and carbon dioxide gas to keep the tissue alive in the liquid, an artificial cerebrospinal fluid. Then she was off, pushing the cart through the hospital with one hand and texting the Allen Institute team with the other. The cart was loaded into a white van modified to safely hold combustible gas canisters. And with that, the bubbling brain bit was on its way. The van threaded through heavy, rain-soaked Seattle traffic back to the lab, where Dee was ready, scalpel in hand.  

After that frustrating start with the uncooperative piece of brain, Dee finally gets enough slices for multiple experiments. A one-hour rest helps the cells recover from the trauma of being separated from the brain. The slices go up to a second-floor lab, where some slices are placed under a powerful microscope and prodded with electricity to study how these live human cells behave. The researchers hope the behavior mimics what the cells did while they were inside their former owner’s skull.

Six scientists sit at “rigs,” each one a microscope mounted inside a black three-sided box. At each rig, a researcher hunts through the woman’s brain tissue for healthy cells — nice and plump, with just the right amount of visibility against the background tissue.

Once they find a good one, the researchers try to latch on with an impossibly thin tube of glass. Called patch-clamp, the technique forces a cellular conversation, which is carried out with electrical signals that move between cells. To get the conversation going requires injecting an electric current into a cell, and then measuring how the cell responds to the artificial message.

Most of these rigs measure the reactions of one neuron at a time. But in the back part of the lab, researcher Lisa Kim pilots a futuristic setup of glistening metal, tangles of blue and black wires and eight needle mounts, all pointing at a different part of a brain slice. While I’m there, this mega-rig is eavesdropping on a kind of party line between seven live neurons. Kim is zipping electricity into each one in turn to see how the signal transmits to its neural neighbors.

The electrical zings of these neurons offer clues about their identities and their relationships; one of the seven cells responds when a neighboring cell gets an electrical zap, a hint that those cells communicated while inside the woman’s head. Other clues come from information about the neurons’ elaborate, gangly shapes created by the signal-sending axons and receiving dendrites. Each neuron reminds me of an impossibly complex map of river tributaries.

An even stronger sense of a cell’s function comes at the end of the patch-clamp experiments. Working the thin glass tube again, a researcher can suck out the nucleus of each live cell. The theft kills the cell but obtains a record of which genes were active when the cell was alive. After Kim finished the game of electrical telephone, she carefully slurped out the nucleus from each of the seven neurons.

All the information gathered from these rigs can help researchers identify neurons that might play a special role in making the human mind. Such scrutiny, for instance, revealed what researchers think is a rare cell called a von Economo neuron, named for the Austrian neurologist who first described the cell type in the 1920s.

The extra-long, extra-spindly neuron was found in live brain tissue donated by a 68-year-old woman who had surgery to remove a tumor. The neuron displayed an unusual electrical response to the current applied to it , Allen Institute scientists and colleagues reported online May 7 at bioRxiv.org. The result was tantalizing, because problems with von Economo neurons are suspected of playing a role in psychiatric conditions and Alzheimer’s disease.

Studies on live human cells also turned up an important difference between humans and mice: A certain kind of human neuron is covered with a protein called an h-channel; in mice, those channels are rare. H-channels help cells respond to electrical signals and can be affected by drugs, including one for epilepsy.

This basic difference, described in 2018 in Neuron , might explain why certain kinds of drugs work differently in the brains of mice and people . More broadly, these newly discovered properties of human neurons might be the things that enable some of the most sophisticated features of our brains.

Taking stock of live human neurons “is essential,” and not just to satisfy humans’ navel-gazing curiosity, says Nenad Sestan, a Yale School of Medicine neuroscientist. Discovering the quirks of human brains “might lead to us understanding one day why we suffer from certain disorders,” Sestan says. Imprecise animal models have stymied research on schizophrenia, autism and Alzheimer’s disease, he says. That’s why studying live, human tissue is so crucial.

From brain to lab

Allen Institute scientists fly into action when a brain sample arrives from a nearby hospital, wringing as much information as they can out of the precious tissue. What the researchers learn about the cells’ behavior, shape and genetic activity is shared publicly in the Allen Brain Atlas. (Bold text shows each step’s duration).

1 to 3 minutes Surgery:   Brain tissue is removed at a Seattle hospital — usually within minutes of a surgeon opening the patient’s skull — and placed into a jar with chilled artificial cerebrospinal fluid bubbling with oxygen and carbon dioxide.

15 to 30 minutes Transport: A specially equipped van speeds the tissue from the hospital to the Allen Institute.

30 to 60 minutes Slice:   The sample is placed on a dish in a bucket of ice, trimmed and sliced into anywhere from six to more than 30 flakes that are each 0.35 millimeters thick.

Distribute:   From each sample, one slice goes into the freezer for future analyses. Every fifth slice is fixed in preservative. The rest are kept alive for more same-day experiments.

1 hour Rest: Live cells recover from the trauma of surgery.

Observe behavior:   Rested cells move to the electrophysiology lab, where “rig” operators study cell behavior with 30 minutes of electrical prodding.

Map cell shape:   Filling some neurons with dye, researchers can see the elaborate projections.

Study the genes:   Thin glass pipettes pull out the nucleus of some neurons so researchers can see which genes were active just before the cells died. 

Weeks to months Manipulation:   Other tests attempt to insert genetic material into cells that stay alive longer than expected. The cells glow for better visibility.

A blow to the ego

But human brains aren’t always so unique. A new result might disappoint people who think that our brains are teeming with specialized neurons that let us talk and think in ways other animals can’t. The overall number of cell types in the human cortex and in the mouse cortex is roughly the same, says a study led by Allen Institute researchers that is in press at Nature . Koch calls the finding “the biggest result, to my mind.”

“People, including scientists, have this strong need [for] human exceptionalism,” Koch says. But the fact that the overall resident population of the human brain and mouse brain is remarkably similar — based on brain tissue from surgeries as well as postmortem tissue — adds to the list of blows to the human ego.

First, Darwin downgraded humans to just another animal on the tree of life. Then, the Human Genome Project shocked us with the news that we have a similar number of genes as mice (and fewer than water fleas). Now, add brain cell types to the list of things that make people more like other mammals. 

The paper coming out in Nature is “historic,” says coauthor Rafael Yuste, a neuroscientist at Columbia University. In terms of understanding how humans compare with other animals, “it’s going to be a before-this and after-this.”

These similarities don’t surprise Suzana Herculano-Houzel, a neurobiologist at Vanderbilt University in Nashville. “We are not special,” she says. Finding that humans and mice have similar types of cells in their brains makes a lot of sense, as does the idea that some cell types and some genes will be species-specific. The question is, she says: “Which of those differences are actually meaningful?”

The explanation for why we’re so smart, then, is not that our brains are teeming with specialized, human-specific neurons. The answer must be found elsewhere. Perhaps it really is in small numbers of rare neurons such as von Economo neurons, or in neurons that haven’t yet been discovered. Still other scientists think that our brainpower might come, in part, from cells in the brain that aren’t neurons, such as the glial cells that perform a range of basic brain jobs that scientists are just beginning to understand ( SN: 8/22/15, p. 18 ).

Or maybe, as Yuste suspects, the answer is the sheer size of our brains compared with our relatively small bodies. Or perhaps our “smarts” are a result of our long life span and the fact that we are immersed in cultures rich with language, literature and customs, as Herculano-Houzel points out.

As Dee did his slicing, neurobiologist Jonathan Ting waited eagerly for his bit of brain. Ting runs experiments that deliver genes to live cells — and he’s kept his cells alive a surprisingly long time.

In his fourth-floor lab, Ting is not happy with the piece he got, calling it “kind of a bloody mess.” But he cuts it up some more and returns the resulting slices to the bubbling solution. Then he pulls what looks like a baking tray out of a nearby incubator, makes a Martha Stewart joke and shows me live brain samples that are weeks old. Some have survived for several months, a hardiness that shocked the researchers when they first began these experiments.

This kind of durability comes in handy as Ting tinkers with how best to infect the cells with viruses. His goal is to use the viruses to deliver genes that make certain groups of live human cells glow. The glow makes it easier to study the cells and, ultimately, to figure out how to change their behavior. To Ting’s delight, he discovered that the virus and its luminescent cargo can be delivered simply by dropping virus-laden liquid on the live brain slices.

As Ting and I look at glowing red and green cells on his microscope’s monitor, he describes the potential of this work with viruses. Not only will the researchers be able to find rare cells in human brains, but they might be able to ultimately control the cells, too. Imagine if a von Economo cell, for instance, could be turned on and off at will with methods that are already under development in animal models.

If the cells are actually involved in a disorder, say, schizophrenia, then this sort of precise control could lead to a targeted treatment that toggles the cells’ activity up or down as needed. It could also ultimately reveal how information flows through these cells, in a way that makes up the mind.

All this tinkering has already turned up big findings. But there is vastly more uncharted territory to explore, Koch says. “The brain is by far, by far the most complex, highly organized piece of active matter anywhere in the universe.”

About this story

Where did the idea come from.

I heard about this project about five years ago at the meeting of the Society for Neuroscience. It wasn’t clear then if the effort would pay off. But with over 100 surgeries and a handful of research papers published, it felt like the story was ripe.

How are we reporting this story?

I had hoped to talk patients and watch surgeries. But that meant getting permission from doctors, hospital administrators, and most importantly, the patient. After several failed attempts, I decided to tell the story with the brain sample itself taking center stage.

I live about four hours south of Seattle. When I got the call that surgery was happening the next morning, I hopped in the car and arrived late that night. I was at Harborview Medical Center just after 9 am to follow a sample of live brain tissue from an operating room to labs across town at the Allen Institute for Brain Science.

I had expected to see frantic speed as scientists raced to study still-living tissue. But I was struck by how much of the process was calm. It was clear that these researchers knew exactly what they needed to do.

— Laura Sanders

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The Most Terrifying Human Experiments In World History

Most of the time, scientific progress is a very positive thing: studies that add to the overall understanding of how the world works. It's an admirable goal, and in reasonable circumstances, arguing against that isn't the easiest thing.

Sometimes, the circumstances are less than reasonable, and the desire to learn and experiment starts to cross the line into the ethically and morally gray. The push toward progress can come with a pretty heavy cost, potentially hurting a lot of people in the process. Human experimentation typically falls along these lines, but even then, there are some projects throughout world history that stand out, and for the worst reasons. Harmful effects on health and dubious consent tend to be pretty common factors in many of the worst of these studies. However, their legacies can sometimes differ, with some achieving infamy while others have managed to slip through the cracks of history.

Similarities and differences aside, though, here are just a few of the most terrifying human experiments ever conducted.

Project 4.1

When it comes to human experiments, Project 4.1 is an odd one. While researchers might have had less of a hand in inflicting terrible circumstances on their subjects, there's still some dubious morality that's worth considering.

For some context, during the 1940s and 1950s, the U.S. used the Marshall Islands as a testing ground for nuclear weapons and research, but it's important to note that these aren't empty, abandoned islands. On the contrary, they'd been inhabited for a long time, yet American tests weren't exactly as carefully planned as you would hope. Even relatively contained tests began raining radiation down on the local population, and public health became a growing concern.

That's where Project 4.1 comes into play, and perhaps its official name — "The Study of Response of Human Beings Exposed to Significant Beta and Gamma Radiation Due to Fallout from High Yield Weapons" — can give some insight into just where the ethics get murky. In effect, the inhabitants of the Marshall Islands became test subjects of convenience, a way for scientists to see the unintended consequences of a mess they had made. None of the locals knew that they were involved in any study; all they knew was that they were being treated for vague illnesses that they were told little about. All the while, of course, they were also dealing with the effects of radiation poisoning — congenital disabilities as well as social tensions — all while their requests for help were largely brushed aside.

The Stanford Prison Experiment

When you think about awful human experiments, there's a pretty good chance that the Stanford Prison Experiment comes to mind, and that's not without good reason. After all, recreating the conditions of a prison, such that reality turns into some "Lord of the Flies" type of nightmare, is more than a little scary.

If you're unfamiliar with it, the Stanford Prison Experiment was a 1971 study conducted by Philip Zimbardo that took a group of male college students and had them simulate the conditions of Stanford County Prison (which was really the basement of the Stanford University Psychology Department). The participants were separated into two groups: prisoners were humiliated from the outset, and guards were put into positions of authority and power. And things quickly devolved from there. Guards began to assert their power through cruelty and both physical and psychological punishment; prisoners experienced deep depression on more than one occasion and, on another occasion, staged a total rebellion (which was meant with even harsher reprisals). The ethics were murky, and the experiment ended after six days despite being planned to last two weeks.

Discussions surrounding the Stanford Prison Experiment have only gotten even more complicated in the years since. From the start, it was likely flawed — selection bias came into play, and even then, some participants admitted to playing up their actions and responses precisely because they knew it was all fake. It's not the best grounds to draw any accurate conclusions.

[Featured image by Philip Zimbardo via Wikimedia Commons | Cropped and scaled | CC BY-SA 4.0 ]

To put it pretty simply, MK Ultra sounds a lot like "The Manchurian Candidate." The idea that Cold War-era communist countries were somehow brainwashing American soldiers overseas was, in fact, a very real concern. And so, naturally, the U.S. government decided to try and weaponize mind control themselves, with all of that research getting rolled up under the purview of MK Ultra .

The project was fairly wide reaching, including just about any experiment that had to do with psychological manipulation. Hypnosis was quite possibly the most tame method, especially considering that electro-shock therapy and exposure to radiation or mind-altering drugs were also on the table. What's more, the actual means by which these experiments were carried out were far from ethical. Participants in these studies often weren't fully aware of exactly what they were signing up for, and even if you were to look past the dubious consent, then you'd find that MK Ultra targeted specific groups. Prisoners and patients in mental hospitals were easy targets, and the stories of their experiences are harrowing — feeling like their bones were melting or losing their ability to understand they were human was just the start.

Unsurprisingly, all of this was done in secret, with the CIA denying they were capable of such things. But word began to get out in the early 1960s, with congressional hearings taking place in the 1970s. Ultimately, those hearings weren't too effective — CIA staff claimed not to remember, and files were very conveniently destroyed — so the exact details might be even worse than those the public is aware of.

Operation Midnight Climax

In 1955, you could easily find an unassuming little house in San Francisco, tucked away on Chestnut Street. Outwardly, there wasn't much you could say about it, but if you started to pull away the curtains, you'd find something much more sinister: This was actually the site of a CIA experiment, one called Operation Midnight Climax .

To be technical about things, Midnight Climax was just one part of MK Ultra, the CIA's wide-reaching experimentation surrounding mind control, but it was awful enough to build up a notoriety all its own. Specifically, it was meant to focus on a particular fascination with LSD, but the execution was hardly scientific. Sex workers were hired to lure unsuspecting victims to the house, and once there, these victims became unwitting subjects, dosed with LSD. Meanwhile, behind the two-way mirror, those in charge of the experiment would just sit and watch. All while apparently having a pretty good time.

The ethics behind this are obviously questionable for many reasons, but it gets even worse. George White — the man who was officially in charge — had intentions rather divorced from drug research: voyeurism. Sure, there were discussions of how to use sex to extract information and the like, but White clearly had more self-serving interests in mind. After all, according to the man himself: "Where else could a red-blooded American boy lie, kill, cheat, steal, rape, and pillage with the sanction and blessing of the All-Highest?" (via The San Francisco Chronicle ).

Nazi experiments

It doesn't need to be said that the Nazis committed plenty of atrocities during World War II (and that's putting it very lightly). But there was more to Nazi atrocities than death camps and gas chambers; the medical experiments were a horror show all their own.

Victims of Nazi science were often Jewish or Romani prisoners in concentration camps — usually those who were deemed unfit to work — and their torture was justified under the Nazi regime as being in search of a way to prove racial supremacy. Hardly an acceptable reason, and it was only made all the worse when you considered what the experiments were. Methods of mass sterilization were a popular area of study — awful for both the fact that said methods were actively tested on innocent victims, and the fact that the intentions were, effectively, genocidal. Work was also done when it came to research on disease, though that work was accomplished by knowingly infecting victims just to see what different cures might do. Then, there was also murder, just to have more bodies to study.

All of it was bad enough to ultimately lead to infamy. After all, it's hard not to think of Nazi experiments and not hear about Joseph Mengele (pictured), known literally as the "Angel of Death" and remembered primarily for his (often lethal) experiments on twins .

When it comes to human experimentation during World War II, the first thing to come to mind is most likely the inhumane science carried out by Nazi doctors. But for as bad as all of that was, Nazi Germany wasn't the only nation guilty of some very twisted experimentation in the 1940s; after all, Japan had Unit 731.

In short, Unit 731 was a secret research branch operating primarily out of regions of China under Japanese control. From its inception in 1938, it focused on testing what the human body could endure. And that meant a whole lot of different things, all of them terribly inhumane and often deadly. Chinese prisoners would sometimes find themselves the subjects of vivisections. The reason why? To see what their internal organs looked like before death. Others were the subjects of vicious frostbite tests, having their limbs frozen, then thawed out by whatever means their captors chose. And that was if their limbs hadn't been amputated for no real reason other than to see what happened. In other cases, victims were subjected to insane situations to see what their bodies could handle: starvation, dehydration, deadly G-forces in centrifuges, or just having large objects dropped on them. Then, there was also weapons testing, which included subjecting people to flamethrowers, bayonets, nerve agents, and exposure to X-ray radiation.

Thousands of people died in those experiments (though the exact statistic remains a mystery), and Unit 731 was kept a secret for decades.

The Aversion Project

Just speaking in general, the racial segregation instituted by apartheid in South Africa during the 20th century was a very obvious problem. But during that time, segregation and oppression were determined by more than just race, and looking to the South African military would find an example in the Aversion Project.

The Aversion Project was an attempt by the South African military to "cure" gay soldiers of their sexuality, and, honestly, the explanation as to why it was so twisted could almost end there. That said, the devil is truly in the details. Many gay men were forced into psychiatric care, where they were given so-called aversion therapy — usually electroshock therapy, in reality, using voltages that were so high they reportedly sent one victim's shoes flying. Not that electricity was the only method being tested — chemical castration, hormone therapy, and unwanted sex-change operations were also on the table and used in thousands of cases. Even outside of the horrific treatments, life in these hospitals hardly focused on healing, with armed guards patrolling the halls and drugs used liberally on all patients — Valium for everyone and a strange "truth drug" that doctors could freely use during interrogations. Far from a welcoming place.

Ultimately, the project was abandoned, and it's done nothing but leave a bitter legacy. The man in charge, Dr. Aubrey Levin, admitted to his failure but not to his human rights violations, and the project itself was just one facet of widespread homophobia at the time.

The Tuskegee Syphilis Study

Syphilis is not something to be taken lightly. Fortunately, its cure is something that sounds very simple nowadays — just a shot of penicillin. So, you would hope there wouldn't be any real reason to deny anyone treatment, right?

Well, if you went back to 1932, you'd find an alarming answer to that question, because that was the start of the Tuskegee Syphilis Study. The point of the study was to track the progression of the disease in hundreds of Black men living in Alabama, which wasn't necessarily ill-intentioned at the outset, as syphilis still didn't have a cure. But come 1947, penicillin was the recognized cure for the disease, and that's where ethics began to turn murky. Physicians had the means to treat hundreds of infected patients, but they just didn't, all because the U.S. Public Health Service valued their experiment over human lives. Officials urged that the men involved in the study continue to receive little more than placebos as their conditions worsened — and that included blindness, insanity, and death on more than a few occasions.

Worse still? The study went on unimpeded for decades, and even upon investigators discovering it in the 1960s, the project was both allowed to continue and explicitly intended to continue until its subjects died. The project didn't come to an end until it was leaked to the public in 1972 — 40 years and over 100 deaths after its inception.

The Guatemala Syphilis Experiment

The Tuskegee Syphilis Study is notorious for good reason; denying treatment to a population simply in the pursuit of cold-hearted academic study with little regard for life is an obvious problem. But American officials took things even further during the lesser-known Guatemala Syphilis Experiment. This wasn't a denial of treatment but a calculated spread of disease.

With the discovery of penicillin as a cure for syphilis during the early 1940s, public health officials wondered at its efficacy and how best to employ it. By the middle of the decade, they'd devised a way to answer that question: building a hospital in Guatemala where they could treat people infected with diseases including syphilis and gonorrhea. But this was far from charity. Instead, they intentionally infected members of the local population — in some cases through the use of infected sex workers, and in other cases by directly injecting people with the disease (typically done to prisoners and patients in psychiatric hospitals). Of course, none of these people had any idea what was happening, nor could they consent to participating in a study that could, honestly, threaten their lives. While it's true that the aforementioned hospital provided treatment to the infected, it's hard to ignore the fact that, over the course of two years, well over a thousand people were affected in the process, including both young children and the elderly.

Radiation experiments

Radiation was a hot topic during the 1940s and 1950s, and understandably so. Scientists at the time had plenty of reasons to learn precisely how dangerous radiation was to the human body. But it's difficult to justify the lengths they went to, because their experiments involved a lot of human experimentation and little consent.

There are several different examples of this — the 1945 Vanderbilt Nutrition Study, for instance, in which hundreds of pregnant women were, without their knowledge, given drugs with traces of radioactive iron. And there was an experiment conducted around the same time in which schoolchildren were fed radioactive calcium, fully backed by the U.S. government.

Perhaps the most egregious, though, were the plutonium injection experiments. And the name tells you most of what you need to know, as researchers wanted to see how radioactive materials were absorbed by the human body. Around 30 supposedly terminally ill patients were unknowingly injected with radioactive plutonium, in some cases at doses far above the lethal limit or with plutonium isotopes that were known to be especially radioactive. Records of these injections were kept secret — very intentionally, to avoid the expected public outcry — and off of normal hospital charts. Consent was only given in, at best, one of those cases, and, to make the situation even more twisted, at least a handful of those patients weren't even terminally ill. One was a 2-year-old child who died less than a year after being injected.

Guidelines for Ethical Conduct of Behavioral Projects Involving Human Participants by High School Students

• Conducting Research
• Schools and Classrooms

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Improving science literacy in the United States requires strengthening science, technology, engineering, and mathematics (STEM) education at the middle school and high school levels. Including a hands-on research experience element in the curricula of scientific disciplines is a crucial part of education in all STEM disciplines, including psychology. Research activities enable students to understand the principles and methods of scientific research in psychology. While engagement in research-based activities at the high school level may be purely educational in nature (that is, the activities do not generate new knowledge), such activities serve to improve science literacy. In addition to enriching the educational experience, engaging in research also enhances critical thinking, creativity, and original thought. Engaging in research also increases knowledge about the scientific process and introduces students to research career options. Furthermore, it provides an opportunity for students to gain firsthand experience about the ethics underlying research with human participants.

These guidelines are scheduled to expire 10 years from (the date of adoption by the APA Council of Representatives). After this date users are encouraged to contact the APA Science Directorate to determine whether this document remains in effect.

Before beginning research projects, it is important that teachers who serve as research supervisors and high school students be knowledgeable about and respectful of the ethical principles underlying research with human participants. Experimentation and research with human participants have and continue to make tremendous contributions to improving people’s lives. However, there have also been several reports of unethical research practices and abuses of human participants in research. It was in response to reports of such abuses in the early 1970s that the U.S. government established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1978, the Commission published the Belmont Report, which outlined three ethical principles that are meant to guide research conducted with humans.

• Respect for persons – individuals should be treated as independent agents, and individuals with diminished independence are entitled to special protections.
• Beneficence – individuals should not be exposed to harm or unnecessary risk, and any benefits should be maximized.
• Justice – individuals should be exposed to fair and equitable procedures, as well as fair distribution of costs and benefits.

Each of these principles, when applied within the research setting, places certain obligations on the researcher. The principle of respect for persons requires voluntary informed consent to be obtained from potential participants. The principle of beneficence requires the maximization of potential benefits and minimization of potential harms associated with participating in research. And finally, the principle of justice focuses on the selection of research participants, ensuring that some classes of people (e.g., persons on welfare, persons belonging to particular racial and/or ethnic minority groups, or persons confined to institutions) are not being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the research question being studied/investigated.

High school students who wish to conduct research with human participants should also be aware of the U.S. government regulations that pertain to the protection of human research participants. Typically, individuals conducting research with human participants at colleges and universities are required to comply with the Department of Health and Human Services, Office for Human Research Protections (OHRP) Code of Federal Regulations Title 45, part 46 (45 CFR 46). These regulations were developed to ensure that the rights and welfare of human research participants are safeguarded, through prior review of proposed research by a committee formed for this specific purpose. High school students who are conducting research projects that are intended for science fair exhibition or publication often must comply with the requirements of the science fair sponsor or publishing journal, which rely on the U.S. government standards and regulations. In addition, high school students and their teachers need to be cognizant of their own school district policies and procedures that may be informed by state and local laws about research being conducted by high school students and involving other students as participants.

Because psychological research with human participants is essential to understanding human behavior and cognition, the American Psychological Association (APA) has established the Committee on Human Research (CHR), whose mission includes developing policies that help protect the rights and welfare of human research participants. To that end, CHR has developed guidelines, described below, for high school students conducting research with human participants. These guidelines were developed in accordance with the rules and regulations mandated by the federal government, as well as the APA Code of Ethics (APA, 2017), specifically standards that pertain to research and publication.

It is important to recognize that this document constitutes “guidelines,” which serve a different purpose than “standards.” Standards, unlike guidelines, require mandatory compliance, and may be accompanied by an enforcement mechanism. This document is meant to be aspirational in intent, and to provide recommendations for the professional conduct of specified activities. These guidelines are not intended to be mandatory, exhaustive, or definitive and should not take precedence over the professional judgment of individuals who have competence in the subject addressed. In addition, given the diversity of laws, regulations, and policies across countries, these guidelines focus only on U.S.- based research.

CHR recommends that students and teachers consider the following guidelines when conducting research with human participants:

• Responsible for the conduct of the student researcher.
• Expected to be familiar with the relevant research literature on the student’s chosen topic, as well as the ethical principles for the conduct of research involving human participants.
• If a well-qualified supervisor cannot be found at the student’s own school, then the student may seek supervision from a qualified individual at another academic institution, including another school, college, or university, or at other types of organizations that have staff with relevant training (e.g., governmental agencies, private firms, or other nonacademic institutions).
• Before beginning a research project, students and supervisors inform themselves of the ethics of research with human participants and relevant U.S. government regulations for the protection of the rights and welfare of human research participants. They should also be knowledgeable about and adhere to school district policies and procedures, as well as state and local laws regarding the conduct of research involving human participants.
• Despite the deceptively impersonal nature of internet-based interactions, in almost all cases, digital information or data is ultimately generated by a person. Thus, the rights and welfare of human participants and their data, although sometimes challenging, should be protected by the judicious application of current policies and regulations, including federal, state, and local laws, and school district policies.
• When using commercially available tools for data collection and data management, students should seek guidance from their respective schools on identifying and using the services of third-party companies whose products and data management policies have been adequately vetted and approved by the school or school district.
• Before beginning a research project, students become familiar with the relevant research literature. This should include previous and current research articles pertaining to the student’s research topic. Preferably, the student finds, reviews, and summarizes the pertinent scientific literature.
• High school administrators and teachers are highly encouraged to form student/teacher/administrator committees to examine all research proposals and review their merit and procedures, including the benefits and risks and the informed consent forms and process. This committee will act in a similar manner to Institutional Review Boards (IRBs), which are convened at colleges and universities to provide oversight of research with human participants, and to ensure that such research follows relevant federal regulations and institutional policies for the protection of human research participants.
• General and specific statements of purpose of the research project
• The research design and analysis plan
• Clear procedures and justification of the chosen method
• The population being studied, including a description of protections in place to safeguard the rights and welfare of potentially vulnerable participants and communities. Teachers and research supervisors should be cognizant of sensitive topics and populations (e.g., child abuse, participants with cognitive impairments) that would not be appropriate for study by a high school student.
• Explanation of the purpose of the research, the time commitment expected of the participants, and a description of the procedures in a way that all potential research participants and parents/guardians can understand.
• Description of any expected benefits from participation.
• Description of any foreseeable risks of harm or discomforts from participation. In cases where the research participants are students themselves, they should not be exposed to any risk greater than the ordinary risks of daily life in school. Although students should not be conducting research that poses foreseeable risks of physical, psychological, or social harm to participants, procedures should be included to indicate what will be done to detect and remediate harmful effects.
• Clear indication that participation is voluntary, that the research participant can discontinue participation at any time, and that refusal to participate will involve no penalty. Opportunities to withdraw with minimum discomfort and stigma, especially with group activities, should be provided. Under no circumstances are potential participants to be exposed to ridicule, force, or excessive group pressure, or undue influence by offering compensation for participation that may be deemed excessive by local oversight bodies, such as an IRB. Undue influence should also be considered when high school administrators or teachers are involved in recruiting students. Furthermore, individuals should not be publicly identified if they choose or decline to participate.
• Describe how confidentiality will be maintained. The confidentiality of the information collected should be preserved and maintained. This includes casual conversations, social media postings, and publication. In most research, the aim is to learn a principle of human behavior, not specific information about any person. For this reason, data should be collected without identifiers to protect the privacy of those who participate in the research. The research participant must be informed if it may be difficult or impossible to maintain full confidentiality about the information collected and be given the choice to not participate. Only with the participant’s full agreement may the student researcher disclose identifiable information about the research participant. Participants should also be informed of the circumstances under which confidentiality may be broken, given state or local laws or school district policies.
• List the name and contact information of a person who can be contacted for answers to questions about the research project, research participants’ rights, and/or report a research-related injury.
• A contingency plan on steps that will be taken in the event that confidentiality of the data is inadvertently breached.
• Once the procedures are completed, misperceptions about the research intent or procedures should be corrected through a debriefing session, especially in projects that used deception, if appropriate.
• Describe who will be authorized to have access to the data, including faculty supervisors and other research team members, if any, as well as how the data will be analyzed, stored, shared, and coordinated with other individuals.
• To ensure that confidentiality is maintained, data collected during the research project must be safeguarded by the teacher or appropriately destroyed.
• Students, teachers, and research supervisors are encouraged to consult with the CHR at the APA. The Committee on Human Research can interpret and provide advice on adherence to these guidelines. In cases where school facilities cannot support advanced research by qualified students, the Committee on Human Research will try to assist students in identifying resources, including local faculty advisors. The Committee on Human Research may be contacted through the American Psychological Association, Science Directorate at 750 First Street, NE, Washington, DC 20002 or [email protected] .
• Schools are strongly encouraged to post a copy of these guidelines in a location where students can easily access them, including making it available online.

American Psychological Association. (2017). Ethical principles of psychologists and code of conduct (2002, amended effective June 1, 2010 and January 1, 2017). https://www.apa.org/ethics/code/

Department of Health and Human Services. (2018). Code of Federal Regulations (CFR), Title 45 (Public Welfare) Part 46 (Protection of Human Subjects). Retrieved from https://www.ecfr.gov/on/2018-07-19/title-45/subtitle-A/subchapter-A/part-46

The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. (1978). The Belmont Report: Ethical principles and guidelines for the protection of human subjects of research. Retrieved from http://videocast.nih.gov/pdf/ohrp_belmont_report.pdf

Guidelines for Ethical Conduct of Behavioral Projects Involving Human Participants by High School Students was updated by the American Psychological Association Committee on Human Research (CHR) from 2020 to 2022. Members of the committee were Jina Huh-Yoo, PhD, Valentina Ivezaj, PhD, Leah Light, PhD, Marguerita Lightfoot, PhD, Maria Marquine, PhD, Karen Saules, PhD, and Sangeeta Panicker, PhD (Staff Liaison). Inquiries about these guidelines should be made to the American Psychological Association, Science Directorate, Office of Research Ethics, 750 First St., NE, Washington, DC 20002, or via email at [email protected] .

Copyright © 2022 by the American Psychological Association. Approved by the APA Council of Representatives, February 2022.

Related resources

• Committee on Human Research (CHR)
• Conducting research
• Human research protections

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