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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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Clinical trials and medical experiments

Published: 30 July 2019

Experimentation is an essential part of scientific medicine. 

Doctors have always conducted investigations and experiments in order to understand the body in sickness and health, and to test the effectiveness of treatments. Medical laboratories carry out experimental research into new techniques and treatments, but at some point developments intended for use on patients have to be tested on people. 

Experimenting with the living—animals and humans—is complex and sometimes dangerous. In their efforts to discover more about diseases and find effective treatments, doctors and researchers have put vulnerable and powerless patients at risk. 

The modern clinical trial—an experiment in which people are the test subjects—has developed over time not only to ensure the optimal conditions to produce valid, scientific results but also to safeguard the rights and well-being of participants.

Clinical trials

In the 1030s, the physician Ibn Sina put forward rules for testing the effect of drugs on patients. One key criterion was that:

The effect of the drug should be the same in all cases or, at least, in most. If that is not the case, the effect is then accidental, because things that occur naturally are always or mostly consistent. Ibn Sina

This remains the essential criterion for any treatment—that it has the same effect on most patients in similar conditions. But testing a drug on one person does not tell you very much. Their response may not be typical, side effects may be the result of an allergy, or their recovery may be due to some external factor. 

Today new medical devices and drugs have to undergo several stages of testing before they reach the final stage of being tested on people. Drug testing and regulation was tightened in the mid-1960s following the impact of thalidomide worldwide. Usually a therapy is tested on animals before clinical trials are permitted.

Participants in clinical trials are carefully selected in order to limit the number of variable factors that might affect the results. For example, only patients at the same stage of a particular condition may be selected in order to see if a new therapy is effective in treating the condition at that stage.

In order to run a clinical trial on people, researchers have to go through a rigorous procedure that includes registering the trial with the authorities and presenting their proposal to an ethics committee, who will decide it the trial is valid and that there are safeguards in place to ensure that participants understand what will happen to them.

Randomised clinical trials

In randomised trials, the test subjects are divided into at least two different treatment groups. Participants are assigned to a group at random. 

One group is usually given the standard treatment for their condition. They are the control group.  People in the other group (or groups) will have the treatment or procedure that is being tested. A randomised trial that has a control group is called a randomised controlled trial (RCT).

If there is no standard treatment, then people in the control group may be given a dummy treatment, called a placebo. A placebo is a treatment with no medical effects. It allows researchers to take into account the psychological influence of experiencing treatment, regardless of what is in the treatment. 

A blind trial is a trial where the people taking part don't know which treatment they are getting. A double blind trial is a trial where neither the researchers nor the patients know what they are getting. The identity of patients in each group is kept secret until the end of the trial. 

What is informed consent?

Legally and ethically, participants in a clinical trial need to have adequate information to allow for an informed decision about participation in a trial. This includes what tests are involved what the risks and benefits may be, how much of your time it will take and what will happen to any of your samples after the trial. 

The modern definition of informed consent came out of the Nuremberg trials, a series of legal trials between 1945 and 1947 to prosecute surviving German war criminals after the Second World War. 

People were shocked by the horrific things done by doctors in the name of medical research and the Nuremberg Code was developed as a result. It is the basis for all rules regarding human experiments, including the requirement for informed consent.

Most countries now have regulatory boards for clinical trials that insist on informed consent before people can participate in clinical trials. 

Before the Nuremburg Code, people in charge of human experiments did not have to tell their patients what they were doing. Some groups of people had no choice in whether or not they participated. 

British troops heading to the South African War (1899–1902) were offered a new typhoid vaccine before it was fully tested and the side-effects understood and eliminated. These side effects were one reason why take-up of the vaccine was so low.  Alongside volunteers, some prisoners were used to test a new cholera vaccine in India in 1897. 

Throughout the 1900s, psychiatrists who wanted to find effective treatments for conditions such as schizophrenia tested experimental convulsive shock therapies on their patients. Researchers had little knowledge of the effects—and patients were not always asked for their consent.

Self-experimentation

Occasionally medical researchers decide to test a new idea or treatment on the most convenient test subject around—themselves. They might do this because the weight of medical opinion is resistant to their idea and they can’t get funding or support to test it any other way. 

Or they might simply have wanted to prove their theory before sharing it with others. Whatever their reasons, self-experimentation has contributed some valuable treatments and techniques to medicine—but it has also gone very wrong.

Do-it-yourself anaesthesia

One field of medicine seems to be full of self-experimenters. The American dentist William Morton was one of several people to try ether as an anaesthetic on himself after witnessing its numbing effects on revellers at the ‘ether frolics’ that were the craze in the 1800s.

The Scottish surgeon James Young Simpson and his friends  were searching for an  alternative general anaesthetic to ether and tested several compounds on themselves, including chloroform. Another celebrated surgeon, Joseph Lister , took a more scientific approach when he and his wife Agnes tested different doses of chloroform on themselves to find the most effective one for his patients.

But perhaps the most surprising case of self-experimentation in anaesthesia was that of the German surgeon August Bier, who decided to find out for himself the effects of cocaine as a local anaesthetic by having his assistant Augustus Hildebrandt inject it into the fluid surrounding the spinal cord. 

But, thanks to a mix-up with the equipment, Bier was left with a hole in his neck that began to leak cerebrospinal fluid. Rather than abandon the effort, however, the two men switched places. Once Hildebrandt had been anaesthetized, Bier stabbed, hammered and burned his assistant, pulled out his pubic hairs and squashed his testicles!

Needless to say both felt the after-effects in subsequent days. But cocaine did prove to be a very effective local anaesthetic and was a forerunner to the modern epidural.

How to cause an ulcer

Australian doctor Barry Marshall had a theory that challenged the medical consensus of the day. He and his colleague, pathologist Robin Warren, were convinced that ulcers were caused by the bacterium Helicobacter pylori, and not—as was the general medical opinion—that they were the result of lifestyle factors such as stress, spicy foods and alcohol.

They had tried to submit their findings to a peer-reviewed journal in 1983, but their paper was turned down. In 1984, Marshall drank a broth containing cultured H. pylori, because he wanted to see the effects on a healthy person. As he explained: "I was the only person informed enough to consent".

He expected to develop an ulcer after perhaps a year, so he was surprised when, only three days later, he developed nausea and halitosis  (bad breath). On day five, he began vomiting. On day eight, an endoscopy showed massive inflammation (gastritis, a precursor to an ulcer) in his stomach, and a biopsy showed that the H. pylori had colonised his stomach. 

On the fourteenth day Marshall began to take antibiotics to fight the H. pylori infection. 

The traditional treatment for severe ulcers was antacids and medications that block acid production in the stomach. Despite this treatment, there was a high recurrence of ulcers. Marshall and Warren’s discovery meant that ulcers could now be cured using antibiotics, preventing years of pain and discomfort and saving money on pharmaceuticals that didn’t work.

Marshall and Warren won the Nobel Prize for Physiology or Medicine in 2005 for their work. 

Animal experiments

Animals have long been used for dissections and medical experiments. For centuries, human dissection was severely restricted and physicians and surgeons relied on animal dissection to learn about human anatomy. 

The Roman physician Galen dissected pigs and monkeys to develop his knowledge anatomy. Although he was restricted by law to dissecting animals, the three years he spent from 158 CE as physician to the gladiators of his home city of Pergamon were a formative period in his life in medicine. The traumatic injuries he regularly encountered gave Galen the perfect opportunity to extend his practical medical knowledge of the human body.

Discussions about whether to experiment on animals has always been part of the debate. Some religious authorities said that animals had no souls and they were under the dominion of mankind, along with the rest of the natural world. The 1600s philosopher and researcher René Descartes (1596-1650) claimed that animals did not feel pain.

The number of experiments on animals increased in the 1800s with the rise of life sciences such as experimental physiology. The French physiologist Claude Bernard used animals in his research and drew criticism for it from opponents, including his own wife and daughters.

Louis Pasteur used rabbits to develop a vaccine for rabies and was the target of protests.

As scientific experimentation on living animals, known as vivisection, grew, so did the anti-vivisection movement. In 1875 the activist Frances Power Cobbe founded the Society for the Protection of Animals. The protests of the early animal rights movement led to the Cruelty to Animals Act of 1876, which regulated animal experimentation in England, Wales and Ireland.

Modern medical research still relies on animals. As well as medical research, testing on animals, primarily rats and mice, is used to assess the safety or effectiveness of products such as drugs, chemicals and cosmetics. Medical researchers are increasingly aware of animal welfare and continue to seek scientific alternatives to animal testing. 

Where the ability to replace animal experiments with alternatives such as tissue cultures, microorganisms or computer models is limited, researchers have tried to reduce the amount of animal testing needed. This is because, apart from the ethical concerns, animal experiments are expensive and (as with all experiments on living organisms) highly complicated.

Both scientific research organisations and animal rights groups promote the use and development of methods of scientific testing that don’t use animals, such as:

in Vitro techniques

An example of a toxicity test in animals that is being replaced is the LD50 test, in which the concentration of a chemical is increased in a population of test animals until 50 percent of the animals die. 

A similar in vitro test is the IC50 test, which tests the cytotoxicity (cell toxicity) of a chemical’s ability to inhibit the growth of half of a population of cells. The IC50 test uses human cells grown in the laboratory and thus produces data that are more relevant to humans than an LD50 value obtained from rats, mice, or other animals.

in silico techniques (computer modeling)

Researchers have developed a wide range of sophisticated computer models that simulate human biology and the progression of disease. Studies show that these models can be used to predict the ways that new drugs will react in the human body without the need for a lot of animal testing.  

Suggestions for further research

• A Harrington (ed.), The Placebo Effect: An Interdisciplinary Exploration , 1997
• J S Hawkins and E J.Emanuel (eds.), Exploitation and Developing Countries: The Ethics of Clinical Research , 2008
• Ruth Chadwick and Duncon Wilson, ' The Emergence and Development of Bioethics in the UK ', in Medical Law Review, Vol. 26 No. 2  

Find out more

What is scientific medicine?

Medicine has always involved scientific and empirical methods—but in the 19th century, new disciplines emerged that radically changed the way medicine was practised.

Science and technology in medicine

Science and technology have changed how medicine is practised around the world.

Understanding the body

In order to understand illness, you have to understand the body and how it works.

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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.

Five Examples of Human Experimentation Leading to Scientific Breakthroughs

From dipping food into a bullet wound to swallowing a bacterial sample, these five examples of "human experimentation" opened new doors for science. Usually a scientist would never begin an experiment by testing in humans. After all, it would seem almost alien to start out immediately poking and prodding people based only on an educated hypothesis. Instead, researchers begin slowly in petri dishes, models or another simulated environment and move up from there.

However, there are times when a scientist has no other option. Believing in his or her own work so much, the only solution is to offer themselves up as a test subject to develop or prove something absolutely groundbreaking. It’s not taking the classical approach, but it gets the job done.

Five researchers make our list of scientists who conducted groundbreaking human experiments (or at least pushed ethical limits with humans) by experimenting on themselves, the unsuspecting or their willing partner.

1. William Beaumont :

Because of William Beaumont’s experimentation on Alexis St. Martin, he is coined "The father of gastric physiology;" however, some scientific historians question the ethics behind the research.

On June 6, 1822, Alexis St. Martin was accidentally shot in the torso. As an Army surgeon, Beaumont treated the wound, but expected St. Martin to die.

Instead, St. Martin recovered, but developed a fistula (open tube leading to his stomach) from his injury which left him unable to return to work. Beaumont hired him as a contracted servant, but found another opportunity for keeping St. Martin around. Due to the way the injury healed, Beaumont was able to observe St. Martin’s digestive processes. But here’s where it gets a little gross – to really gain insight into digestion, Beaumont would tie some string around a piece of food and insert it into the hole, observing it every few hours to see how well it had been digested. He also extracted gastric acid and continued experimentation after St. Martin left. Beaumont’s research led to an understanding that stomach acid plays a significant role in digestion and that chewing was not the primary process.

2. George Otto Gey :

Ok, this example doesn’t really involve experimenting on a person directly, but it is a famous case that seemed to defy human ethics. Gey was the scientist behind the development of the HeLa cell line, which is the first immortalized human cell line used for research. The reason it’s a touchy subject is because Henrietta Lacks, a cancer patient, was the unsuspecting source of these cells, and her surviving family received no financial gain.

In 1951 Lacks’s treating physician sent a biopsy to Gey’s lab. The cells grew at an astounding rate and were later sold to other researchers. The HeLa cell line contributed to other discoveries such as developing vaccines for human papillomavirus.

As fate would have it, Gey was diagnosed with pancreatic cancer. And as a committed researcher, right before an emergency surgery, he instructed doctors to take a biopsy and attempt to grow another line of cells for research. Unfortunately, his wishes were ignored.

3. Science for the Masses (SFM):

In 2015, a group of independent researchers, described as “biohackers,” collaborated on a project to test the possibility of night vision. Using information from Totada R. Shantha’s 2012 patent for using Chlorin e6 (Ce6) as a treatment for night blindness, the Science for the Masses team set out to experiment on one of their own. Gabriel Licinia offered himself to be the test subject, while Jeffrey Tibbetts, another SFM member, pipetted 50 microliters of their Ce6 mixture into the conjunctival sack of Licinia’s eye. Their mixture was based on the original patented formula; however, the SFM team added insulin and dimethylsulfoxide to improve the blend. The experiment worked.

When tested at night in the woods, Licinia was able to identify people and shapes at given distances 100% of the time, while the control group was only able to identify objects one third of the time. This experiment, however, was meant for informational purposes. And the SFM team cautions others not to try this on their own since increasing light amplification might cause negative side effects. With that said, the SFM team also said it may open opportunities to grant soldiers improved night vision.

4. Jonas Salk:

While Jonas Salk followed conventional experimental methods, he makes the list since he and his family were among the initial test subjects. Salk is famed for developing a polio vaccine using a “killed-virus.” Originally, when proposing the idea, he was insulted by other researchers, even called “a mere kitchen chemist” by virologist Albert Sabin. Despite some of the negative press, Salk was developing his vaccine faster than developers of live-virus vaccines, and March of Dimes resources soon went to support his endeavor.

After effectively inoculating monkeys first, he volunteered himself and family for the next step. In 1952, Salk boiled some needles in his kitchen stove and administered the vaccine to himself, his wife and three kids. Around that same time, he also partnered with the D.T. Watson Home for Crippled Children and the Polk State School, administering the vaccine to a small sample of children. The results were successful, and after gaining more public support, one of the biggest American clinical trials began. Between April and of June 1954 there were 1.8 million “polio pioneers.”

But even more heroic than volunteering himself and family to literally save millions, Salk opted not to patent the vaccine and received no compensation for his discovery. Salk was once asked about who owned the patent, and he replied, “Well, the people, I would say. There is no patent. Could you patent the Sun?”

5. Barry J. Marshall and J. Robin Warren:

We started with the stomach, and we’re ending with the stomach with Barry Marshall and J. Robin Warren. This is perhaps the best example of self-experimentation leading to brilliant discoveries.

Warren was a pathologist who had been studying gastritis, which can lead to stomach ulcers and gastric cancer, and Marshall began taking an interest in the work. The two noticed that the usual drug treatments that blocked gastric acid would only work temporarily, and patients would often relapse. Together they began to study a spiral bacterium ( Heliobacter pylori ) that appeared to be associated with stomach ulcers. However, the suggestion that bacteria could live in the acidic conditions of the stomach seemed preposterous to most scientists. To make things more difficult for Warren and Marshall, during their research, the pair was unable to infect piglets to prove their theory. But being so sure of their research, Marshall drank from a dish containing cultured H. pylori . Of course he did not do this before having an endoscopy to show his gastric conditions were normal. After ingesting the culture, Marshall began experiencing the initial symptoms: nausea and halitosis, which crept up only three days later. Five days later he began vomiting. And on the eighth day, Marshall had a second endoscopy and biopsy, revealing he had gastritis and H. pylori was present. To counter the infection, Marshall began taking antibiotics.

Their risky move was rewarded in 2005 with a Nobel Prize in Physiology or Medicine for the discovery of Heliobacter pylori and its role in gastritis and peptic ulcer disease.

Do you think any other scientists make the list? Comment below and share their stories!

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Science-Based Medicine

Exploring issues and controversies in the relationship between science and medicine

Ethics in human experimentation in science-based medicine

Science-based medicine depends upon human experimentation. Scientists can do the most fantastic translational research in the world, starting with elegant hypotheses, tested through in vitro and biochemical experiments, after which they are tested in animals. They can understand disease mechanisms to the individual amino acid level in a protein or nucleotide in a DNA molecule. However, without human testing, they will never know if the end results of all that elegant science will actually do what it is intended to do and to make real human patients better. They will never know if the fruits of all that labor will actually cure disease. However, it is in human experimentation where the ethics of science most tend to clash with the mechanisms of science. We refer to “science-based medicine” ( SBM ) as “based” in science, but not science, largely because medicine can never be pure science. Science has resulted in amazing medical advances over the last century, but if there is one thing that we have learned it’s that, because clinical trials involve living, breathing, fellow human beings, what is the most scientifically rigorous trial design might not be the most ethical.

About a week ago, the AP reported that experiments and clinical trials that resemble the infamous Tuskegee syphilis study and the less well known, but recently revealed Guatemala syphilis experiment were far more common than we might like to admit. As I sat through talks about clinical trial results at the Society of Surgical Oncology meeting in San Antonio over the weekend, the revelations of the last week reminded me that the intersection between science and ethics in medicine can frequently be a very tough question indeed. In fact, in many of the discussions, questions of what could or could not be done based on ethics were frequently mentioned, such as whether it is ethically acceptable or possible to do certain followup trials to famous breast cancer clinical trials. Unfortunately, it was not so long ago that such questions were answered in ways that bring shame on the medical profession.

More than Tuskegee and Guatemala

The most notorious of highly unethical human experiments outside of Nazi Germany and the Japanese empire during World War II is the infamous Tuskegee syphilis study . This study, conducted by our very own Public Health Service (PHS) was conducted between 1932 and 1972 and examined the natural progression of untreated syphilis in poor black men who received free health care from the government. In 1932, when this study was conceived it was not inherently unethical. At the time there were precious few treatments for syphilis, and none of them worked very well. Consequently, observing the progression of syphilis, using the treatments available at the time, and following the subjects prospectively constituted a reasonable trial design. However, in the late 1930s and early 1940s, penicillin became available, and by 1947 was the standard of care for treating syphilis. When campaigns to eradicate syphilis came to the county in which most of the subjects, study researchers prevented their subjects from participating. In essence, even after an effective treatment for syphilis had become widely available, study still researchers denied it to their subjects. By the end of the study in 1972, of the original 399 men in the study, 28 had died of syphilis; 100 were dead of related complications; 40 wives had been infected with syphilis; and 19 children had been born with congenital syphilis. The rationale for not providing effective treatment for these men and even discouraging them from undergoing such treatment? This :

Such individuals seemed to offer an unusual opportunity to study the untreated syphilitic patients from the beginning of the disease to the death of the infected person. An opportunity was also offered to compare the syphilitc process uninfluenced by modern treatment, with the results attained when treatment had been given.

Worse, there was no informed consent, and considerable inducements were offered to the men to join the study.

The Tuskegee syphilis study, unfortunately, is not the only abuse committed by the PHS. About six months ago, it was revealed that these sorts of experiments had been more widespread than commonly believed. Indeed, in the 1940s in Guatemala, the PHS had gone one better in that they had deliberately infected prison inmates in Guatemala with syphilis. As I described in a lot more detail when the revelations first hit the press, prostitutes who had tested positive for syphilis were recruited to visit the men in prison. The hypothesis to be tested was whether prophylactic penicillin treatment could prevent infection, and the other purpose was to define the response of syphilis to penicillin treatment. Again, there was no real informed consent. Worse, subjects were intentionally infected with a potentially fatal disease. True, they were treated, but treatment is not 100% effective, and one has to wonder if the prisoners, a vulnerable population, understood the nature of the risks they were being induced to take.

On Sunday, AP medical writer Michael Stobbe published a long article detailing the sordid history of medical research in the U.S. before the 1970s. His timing was not coincidental, because on Tuesday in Washington, DC, there was a meeting of a presidential bioethics committee, the Commission for the Study of Bioethical Issues, triggered by the revelations last fall about the Guatemala syphilis experiment 65 years ago. Those revelations led the AP to do an exhaustive review of reports from medical journals and press clippings, and the AP found at least 40 studies similar to the Guatemala syphilis study in that patients were put at risk for serious disease or, even worse, healthy people were intentionally made ill to study disease. Some of these abuses are well known, others much less so.

Here are some examples from the AP article:

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.

Stobbe goes on to point out the “Holy Trinity” of news stories in the 1960s and early 1970s that brought to light the sorts of activities that we now consider abuses in medical research. The last of these was, of course, the Tuskegee syphilis study. The first of these occurred in 1963, when it came to light that researchers had injected cancer cells into elderly debilitated patients at the Jewish Chronic Disease Hospital in Brooklyn to discover whether their bodies would reject them. With our knowledge of tumor immunology now, we can look back on this experiment and know that the odds of any harm were quite small because tumors, with very, very rare exceptions, are not transplantable in humans. Our bodies recognize cells from another person to be foreign, whether they are cancer or not, and quickly destroy them. However, at the time, based on what was known, undoubtedly the scientists thought that there was at least a chance that these tumor cells would form cancers in the patients into whom they were injected, the denial of the hospital director who deemed the cells “harmless,” notwithstanding. (Indeed, the hospital director strikes me as either lying or deluded.) Otherwise, why seek to answer the question? Just as bad, there was no informed consent, the justification being that the cells were thought to be “harmless.” More details can be found here . The outcome was that the Board of Regents censured the researchers and suspended the licenses of two of the doctors involved. Later, however, they stayed the suspensions and instead put the doctors on probation for one year. There were no repercussions for the hospital or for Memorial Sloan-Kettering Cancer Center, where one of the investigators was on faculty.

The third of the “Holy Trinity” was an infamous experiment in Staten Island at the Willowbrook State School, which was a school for children with mental retardation. During the mid-1960s, children there were intentionally infected with hepatitis in order to determine whether gamma globulin could cure it. Besides the targeting of a vulnerable population (children and teens with profound mental retardation), this study demonstrated a number of problematic issues as well . First, the investigators rationalized infecting these children by rationalizing that hepatitis was so endemic in the facility due to the fact that most of the children there were incapable of being toilet trained that over 70% of new residents became infected within a year. This, of course, leads to the obvious question , namely: If that were the case then why not study the effect of gamma globulin on children who were infected normally? More disturbing, again investigators played fast and loose with informed consent, the form being worded in a vague and ambiguous manner that played down the fact that the children were going to be intentionally infected with hepatitis and implying that the serum they would be given would be an experimental vaccine. Finally, as is the case in many such studies, there was an element of coercion. Willowbrook at the time was very crowded, with long waiting lists for children to be admitted. At times, there was only room in the experimental wing. For parents who could not afford to take care of their children, this situation could bring considerable pressure to bear to “persuade” them to “do the right thing.”

Changing ethics

In studying the history of medicine and clinical trials, what never ceases to amaze me is the different attitudes that physicians and scientists had towards their human subjects not all that long ago. Remember, it was primarily in the 1960s and 1970s when attitudes began to change. Before the 1970s, for instance, researchers thought little of using prisoners for experiments, even though prisoners are correctly considered a population that is vulnerable and for whom true informed consent without coercion is difficult to obtain without special attention to making it happen. Indeed, in his news story Stobbe recounts an anecdote of a man at Holmesburg Prison in Philadelphia who agreed in exchange for cigarette money to have the skin peeled off of his back and searing chemicals painted on the open wounds in order to test a drug. Similarly, as the Willowbrook story shows us, it was not really all that long ago when scientists apparently felt justified in infecting profoundly mentally retarded children with hepatitis on the basis of at best dubious ethical justification.

Arguably, this willingness to experiment on children who were not normal and who were never going to be able to contribute to society was a holdover from the eugenics movement earlier in the 20th century. It’s important to remember that, however much eugenics was discredited by the Nazis, prior to the Holocaust Hitler was actually quite the admirer of American eugenics policies, drawing inspiration from them. Another factor that is frequently invoked as an explanation for the willingness of American scientists to flout ethical considerations is war, particularly World War II and then the Cold War, the resulting idea that it was “us against them,” and that for us to win would require shared sacrifice in the name of the nation. After all, the scientific primacy of the U.S. was viewed as one of the most critical sources of our economic and military strength. Moreover, the concept of the Cold War could be generalized to other “wars,” such as the “war on disease” or the current “war on cancer” that I’ve written about twice in the last month. As Stobbe put it:

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.

There was clearly also more than a little hubris at play as well:

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.

Finally, with the rise of large pharmaceutical companies in the 1940s and 1950s, increasingly there was more of a profit motive than a purely scientific one. Drugs needed to be tested, and prisoners provided a convenient source of young, healthy men upon which to test new products. Hubris, profit, and a wartime attitude that sacrificing for the good of the nation all swirled together into a mixture toxic to medical ethics during World War II and well into the postwar period. In having defeated the Nazis, we failed to learn a lesson from what had happened in Germany, where one of the most technologically and medically advanced societies then on the face of the earth did horrible things in the name of its ideology.

Yes, it is true that American scientists did not intentionally expose prisoners to freezing water in experiments designed to find better ways of rewarming pilots shot down over frigid waters or sailors who survived the sinking of their ship, as Nazi doctors did. It is also true that American scientists did not intentionally irradiate men’s testicles and women’s ovaries in order to develop a means of rapid sterilization, causing horrific bowel and bladder complications, especially in women, as Nazi scientists did, although American scientists did subject many to various radioactive substances in the name of research. Nor did American scientists inject dyes into the eyes of children in order to try to turn them blue, as Dr. Mengele did. On the other hand, American scientists did, as we have seen, intentionally infect prisoners and mentally retarded children (the same sort of children that the Nazis would have called “life unworthy of life”) with diseases and then treat them, just as Nazi physicians intentionally infected concentration camp inmates with various diseases in order to determine the efficacy of different treatments or as Japanese physicians did when they intentionally broke the limbs of prisoners and contaminated them with bacteria-laden dirt. American offenses were different in scale and horror, but not significantly different in kind. Unfortunately, it was not until the 1970s, years after the international Helsinki Declaration was first published, until the Belmont Report was adopted and then not until the 1990s when The Common Rule became the basis of all federal regulations protecting human research subjects, as I have described before .

Could it happen again?

Fortunately, as one who now participates in clinical trials and clinical trial development, given the current level of regulation on human subjects research by the federal government, I have a hard time imagining how abuses such as the one’s I’ve described could happen again now. The amount of paperwork, regulation, and oversight of clinical trials has become so burdensome and complex that sometimes I wonder why I or anyone else would want to continue doing clinical research. Unfortunately, Stobbe doesn’t sound too optimistic. Actually, it’s not so much Stobbe, but rather the presidential Commission for the Study of Bioethical Issues, as Stobbe documents in a followup story :

Speakers noted that over the last several decades, as many as 1,000 rules, regulations and guidelines have been enacted worldwide to ensure the ethical conduct of medical research. In the United States, there are rules to protect people in every study done by federal scientists, funded by federal agencies or those testing a product requiring federal approval to be sold. But that oversight is inconsistent — ethical rules can vary among federal agencies. What’s more, if federal funding or review is not involved, an unethical study could be done and no one in authority would ever know about it. “We have a leaky system,” said Eric Meslin, director of the Indiana University Center for Bioethics. Dr. Robert Califf, Duke University’s vice chancellor for clinical research, agreed there are weaknesses. “It’s night and day and what you could do in the ‘good old days’ with no one knowing about it. But there’s no 100 percent guarantee. There still will be bad things that will happen,” he said.

In terms of pharmaceutical companies, there are clearly loopholes when it comes to overseas studies. Indeed, pharmaceutical companies have been doing more and more studies overseas. Although federal law states that such studies, if they are funded by the federal government or if they are to be used as part of an application for FDA approval of a drug, that is not always enough of a guarantee of oversight :

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.

Clearly, this is an unacceptable level of oversight, particularly outside of developed countries, such as those in Europe, where clinical trial oversight is comparable to that in the U.S.

Ironically, two examples come to mind of clinical trials that show the holes in our regulatory system for human subjects protection, both of which I have written about right here on SBM before. The first trial was a trial of homeopathic remedies for infants with infectious diarrhea in Honduras, as I wrote about here and Wally Sampson wrote about here . At the time I couldn’t figure out how the investigators at the University of Washington managed to get this study through their IRB, but somehow they did, demonstrating that an IRB is not a guarantee against the approval of totally unethical and scientifically worthless experiments. Fortunately, as far as I can tell, no infant was injured, but the potential was definitely there. Then, let’s not forget the Gonzalez trial, a trial of a regimen of what can best be described as pure quackery consisting of up to 150 supplement pills a day, various nutritional pseudoscience, and daily (or more) coffee enemas. The results were devastating , in that subjects on the standard-of-care chemotherapy arm lived three times longer than those on the Gonzalez protocol arm. Such is the effect of the National Center for Complementary and Alternative Medicine ( NCCAM ) on research ethics.

The more disturbing example is Mark and David Geier, the father-son tag team of anti-vaccine activists who fervently believe that mercury in vaccines causes autism and somehow came up with an idea that can only be described as dangerously wacky, namely that by suppressing testosterone with a powerful drug (Lupron) they could make the quackery known as chelation therapy “work better” at chelating mercury from the brains of autistic children. The reason? Because “testosterone sheets” bind mercury and keep it from being chelated! In pursuing this research, the Geiers have created an IRB stocked with their cronies and fellow anti-vaccinationists to “oversee” the research, as Kathleen Seidel has so thoroughly documented . In the process, autistic children were subjected to a powerful drug that depresses their sex hormone levels, which is why its use is often referred to as “chemical castration.” Predictably, Anne Dachel, Media Editor over at the anti-vaccine crank blog Age of Autism, has leapt all over this story as “evidence” that vaccines must be dangerous and that unethical scientists have been lying all along about the science showing tthat there is no evidence that vaccines cause autism:

Either Stobbe is a naïve and trusting soul and can’t consider that the same government that allowed horrific medical experiments in the past also allowed our children to become vaccine guinea pigs, or he’s afraid of an issue that’s just too controversial to talk about here and now. It’s much safer to attack what went on in the last century. Maybe 70 years from now, some enterprising reporter will bring up the ethics of injecting known neurotoxins in pregnant women, babies, and small children. Maybe around 2080, they’ll ask why no one ever demanded independent studies on the cumulative effect of so many vaccines, so soon, on the health of a baby. Or why there was never a simple vax-nonvax comparison study looking at autism rates.

Or maybe in 2050, Dachel will understand that this is the sort of work that’s been replicated so many times and done in so many different countries that even if you were to throw out all the U.S. data it wouldn’t change the conclusion that vaccines do not cause autism. She also overlooks the fact that the vast majority of the studies that have failed to find a link between vaccines and autism were performed after the adoption of the Common Rule and much-increased federal oversight over clinical trials. Of course, stories like Stobbe’s make it easier for cranks to attack the entire U.S. clinical research enterprise as corrupt and unethical. However, that is not the reason why we need to close the loopholes in our current clinical trial regulations. We need to do it because it is the right thing to do.

We at SBM argue that medicine should be based on science, rather than be a science, because we realize that medicine can never be completely scientific. There are too many human variables, not the least of which are patient values, individual patient situations, and resources. Another reason is the clinical trial process itself. Sometimes the most scientifically rigorous clinical trial design is not the most ethical design; indeed, sometimes it might be downright unethical. One example is, as I have pointed out , the aforementioned study of vaccinated versus unvaccinated children that seems to be every anti-vaccine activist’s most fervent dream. The most scientifically rigorous design for such a study would be a randomized, double-blind, placebo-controlled trial. However, such a trial would leave half of its participants completely unprotected against potentially deadly childhood infectious diseases, making it totally unethical to perform, even if it could be scientifically and fiscally justified based on existing preliminary data, which it really cannot.

Perhaps a better example is how placebo-controlled trials have almost gone the way of the dodo in cancer chemotherapy trials. Most oncology trials are now designed to test a new drug against the current standard of care or the new drug plus the standard of care versus standard of care alone. This is because our ethical considerations have evolved such that we now no longer consider giving placebos to cancer patients to be ethical unless there truly is no existing effective treatment for their cancer or if we truly do not know if the proposed treatment is better than observation alone and observation alone is currently the standard of care. As I have described before, in clinical trials, there must be clinical equipoise ; i.e., based on the scientific evidence as it is known at the time the trial begins, a reasonable scientific assessment of the risks and benefits must conclude that the risks to the experimental group are either minimal or outweighed by the potential benefits. Here’s another thought to chew on. Experiments in which people were intentionally exposed to infectious agents and then subjected to various treatments to cure the disease thus caused are potentially the most scientifically rigorous way of all to test such treatments in humans because they allow control of the start of the infection, the amount of bacteria injected, and many other variables that can’t be so easily controlled in “wild” cases of infectious disease. However, because such experiments violate the precept of, “First, do no harm,” they are utterly unethical and now properly condemned by any physician with a shred of ethics. That we should require laws, rules, and regulations to prevent such unethical experiments by scientists is unfortunately, but scientists are no different than any other person. Not all of them are ethical; some are completely unethical. Some can be corrupted.

There will always be unethical scientists, at least as long as there are unethical people. That’s why we need laws to protect human subjects. However, we must also remember that the protection of human subjects is a balancing act. Go too far in the direction of lax regulation, and incidents such as those described in Stobbe’s article will start to happen again. Go too far in the other direction, and the pace of discovery will grind to a halt. Key to finding the balance is to respect patient autonomy and to provide true informed consent that accurately balances risks versus benefits and to protect patients from any form of coercion. Doing so without making the clinical trial process so onerous that researchers flee the field while at the same time protecting patients from foreseeable harms will be the challenge.

Dr. Gorski's full information can be found here , along with information for patients. David H. Gorski, MD, PhD, FACS is a surgical oncologist at the Barbara Ann Karmanos Cancer Institute specializing in breast cancer surgery, where he also serves as the American College of Surgeons Committee on Cancer Liaison Physician as well as an Associate Professor of Surgery and member of the faculty of the Graduate Program in Cancer Biology at Wayne State University. If you are a potential patient and found this page through a Google search, please check out Dr. Gorski's biographical information, disclaimers regarding his writings, and notice to patients here .

• Posted in: Clinical Trials , Medical Ethics , Pharmaceuticals , Science and the Media

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• 25 April 2018

The ethics of experimenting with human brain tissue

• Nita A. Farahany 0 ,
• Henry T. Greely 1 ,
• Steven Hyman 2 ,
• Christof Koch 3 ,
• Christine Grady 4 ,
• Sergiu P. Pașca 5 ,
• Nenad Sestan 6 ,
• Paola Arlotta 7 ,
• James L. Bernat 8 ,
• 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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5 Unethical Medical Experiments Brought Out of the Shadows of History

Prisoners and other vulnerable populations often bore the brunt of unethical medical experimentation..

Most people are aware of some of the heinous medical experiments of the past that violated human rights. Participation in these studies was either forced or coerced under false pretenses. Some of the most notorious examples include the experiments by the Nazis, the Tuskegee syphilis study, the Stanford Prison Experiment, and the CIA’s LSD studies.

But there are many other lesser-known experiments on vulnerable populations that have flown under the radar. Study subjects often didn’t — or couldn’t — give consent. Sometimes they were lured into participating with a promise of improved health or a small amount of compensation. Other times, details about the experiment were disclosed but the extent of risks involved weren’t.

This perhaps isn’t surprising, as doctors who conducted these experiments were representative of prevailing attitudes at the time of their work. But unfortunately, even after informed consent was introduced in the 1950s , disregard for the rights of certain populations continued. Some of these researchers’ work did result in scientific advances — but they came at the expense of harmful and painful procedures on unknowing subjects.

Here are five medical experiments of the past that you probably haven’t heard about. They illustrate just how far the ethical and legal guidepost, which emphasizes respect for human dignity above all else, has moved.

The Prison Doctor Who Did Testicular Transplants

From 1913 to 1951, eugenicist Leo Stanley was the chief surgeon at San Quentin State Prison, California’s oldest correctional institution. After performing vasectomies on prisoners, whom he recruited through promises of improved health and vigor, Stanley turned his attention to the emerging field of endocrinology, which involves the study of certain glands and the hormones they regulate. He believed the effects of aging and decreased hormones contributed to criminality, weak morality, and poor physical attributes. Transplanting the testicles of younger men into those who were older would restore masculinity, he thought.  

Stanley began by using the testicles of executed prisoners — but he ran into a supply shortage. He solved this by using the testicles of animals, including goats and deer. At first, he physically implanted the testicles directly into the inmates. But that had complications, so he switched to a new plan: He ground up the animal testicles into a paste, which he injected into prisoners’ abdomens. By the end of his time at San Quentin, Stanley did an estimated 10,000 testicular procedures .

The Oncologist Who Injected Cancer Cells Into Patients and Prisoners

During the 1950s and 1960s, Sloan-Kettering Institute oncologist Chester Southam conducted research to learn how people’s immune systems would react when exposed to cancer cells. In order to find out, he injected live HeLa cancer cells into patients, generally without their permission. When patient consent was given, details around the true nature of the experiment were often kept secret. Southam first experimented on terminally ill cancer patients, to whom he had easy access. The result of the injection was the growth of cancerous nodules , which led to metastasis in one person.

Next, Southam experimented on healthy subjects , which he felt would yield more accurate results. He recruited prisoners, and, perhaps not surprisingly, their healthier immune systems responded better than those of cancer patients. Eventually, Southam returned to infecting the sick and arranged to have patients at the Jewish Chronic Disease Hospital in Brooklyn, NY, injected with HeLa cells. But this time, there was resistance. Three doctors who were asked to participate in the experiment refused, resigned, and went public.

The scandalous newspaper headlines shocked the public, and legal proceedings were initiated against Southern. Some in the scientific and medical community condemned his experiments, while others supported him. Initially, Southam’s medical license was suspended for one year, but it was then reduced to a probation. His career continued to be illustrious, and he was subsequently elected president of the American Association for Cancer Research.

The Aptly Named ‘Monster Study’

Pioneering speech pathologist Wendell Johnson suffered from severe stuttering that began early in his childhood. His own experience motivated his focus on finding the cause, and hopefully a cure, for stuttering. He theorized that stuttering in children could be impacted by external factors, such as negative reinforcement. In 1939, under Johnson’s supervision, graduate student Mary Tudor conducted a stuttering experiment, using 22 children at an Iowa orphanage. Half received positive reinforcement. But the other half were ridiculed and criticized for their speech, whether or not they actually stuttered. This resulted in a worsening of speech issues for the children who were given negative feedback.

The study was never published due to the multitude of ethical violations. According to The Washington Post , Tudor was remorseful about the damage caused by the experiment and returned to the orphanage to help the children with their speech. Despite his ethical mistakes, the Wendell Johnson Speech and Hearing Clinic at the University of Iowa bears Johnson's name and is a nod to his contributions to the field.

The Dermatologist Who Used Prisoners As Guinea Pigs

One of the biggest breakthroughs in dermatology was the invention of Retin-A, a cream that can treat sun damage, wrinkles, and other skin conditions. Its success led to fortune and fame for co-inventor Albert Kligman, a dermatologist at the University of Pennsylvania . But Kligman is also known for his nefarious dermatology experiments on prisoners that began in 1951 and continued for around 20 years. He conducted his research on behalf of companies including DuPont and Johnson & Johnson.

Kligman’s work often left prisoners with pain and scars as he used them as study subjects in wound healing and exposed them to deodorants, foot powders, and more for chemical and cosmetic companies. Dow once enlisted Kligman to study the effects of dioxin, a chemical in Agent Orange, on 75 inmates at Pennsylvania's Holmesburg Prison. The prisoners were paid a small amount for their participation but were not told about the potential side effects.

In the University of Pennsylvania’s journal, Almanac , Kligman’s obituary focused on his medical advancements, awards, and philanthropy. There was no acknowledgement of his prison experiments. However, it did mention that as a “giant in the field,” he “also experienced his fair share of controversy.”

The Endocrinologist Who Irradiated Prisoners

When the Atomic Energy Commission wanted to know how radiation affected male reproductive function, they looked to endocrinologist Carl Heller . In a study involving Oregon State Penitentiary prisoners between 1963 and 1973, Heller designed a contraption that would radiate their testicles at varying amounts to see what effect it had, particularly on sperm production. The prisoners also were subjected to repeated biopsies and were required to undergo vasectomies once the experiments concluded.

Although study participants were paid, it raised ethical issues about the potential coercive nature of financial compensation to prison populations. The prisoners were informed about the risks of skin burns, but likely were not told about the possibility of significant pain, inflammation, and the small risk of testicular cancer.

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Scientific Research and Experimenting on Human Beings

• First Online: 01 September 2019

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• Laura Palazzani 2  

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Experimentation is essential in scientific research for the advancement of knowledge. The objective of experimentation is in itself good, insofar as it aims at improving the conditions of human’s health and wellbeing, but it should be adequately justified in relation to the protection of the interests and fundamental rights of the subject being experimented on. The chapter analysis the main ethical requirements of experimentation on human beings in general, focusing on particularly vulnerable categories (minors, women, people in developing Countries). A special focus is dedicated to innovative treatments, early access, unexperimented or not yet experimented drugs and the so called ‘compassionate use’.

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Starting from the Nuremberg Code (1947), through the Declaration of Helsinki (1964 and successive revisions) and the drawing up of the guidelines for clinical practice (Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects , adopted in 1993 with successive revisions; Good Clinical Practice approved by The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use in 2002), up to the documents of international and community importance, with different levels of bindingness. In particular the following deserve mention: UNESCO ( 2005 ); Council of Europe ( 1997 , 2004 ); Regulation of the European Union No. 536/2014 of 16 April 2014 on clinical trials of drugs for human use, which repeals directive 2001/20/EC. In this context see also: European Medicines Agency (EMA) ( 2016 ); World Health Organization (WHO) ( 2002 , 2011 ).

On this topics see the Opinions of the Italian Committee for Bioethics ( 1992a , b , 2009 , 2010a , c ).

On this topics see Emanuel et al. ( 2011 ); Council of Europe, Committee on Bioethics (DH-BIO) ( 2012 ).

See documents on the topics on an European level: European Medicines Agency (EMA) ( 2008 , 2012 ); European Commission ( 2013 ); European Commission ad hoc group ( 2008 ). The main Opinions on the topics in Europe: Nuffield Council on Bioethics ( 2015 ); U.K. Medical Research Council ( 2004 ); Italian Committee for Bioethics ( 2012 ); Working Party of Research Ethics Committees in Germany ( 2010 ). On an international level: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ( 2000 ); International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ( 2016 ). In USA: American Academy of Paediatrics – Committee on Bioethics ( 2016 ); U.S. National Academy of Sciences (Committee on Clinical Research Involving Children) ( 2004 ); U.S. National Academy of Sciences (Committee on Paediatric Studies-Institute of Medicine) ( 2012 ); U.S. National Institutes of Health ( 2016 ); U.S. Presidential Commission for the Study of Bioethical Issues ( 2013 ).

Wendler ( 2006 ), pp. 229–234.

Miller and Nelson ( 2006 ), pp. S25–S30.

The regulation on international level: UN Convention of the Rights of the Child , 1989; Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine , 1997; Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research , 2005. Regulation on European level: Charter of Fundamental Rights of European Union , 2000 (2000/C 364/01); Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data; Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance); Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (Text with EEA relevance); Regulation (EU) 679/2016 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation); European Parliament Resolution of 15 December 2016 on the regulation on paediatric medicines (2016/2902(RSP)).

While in 1977 the Food and Drug Administration (FDA) in its General Considerations for the Clinical Evaluation of Drugs and in 1982 the World Health Organisation in its Proposed International Guidelines recommended the exclusion of women from experimentations, it is in 1988 that the FDA in its Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Application recommends the analysis of data differentiated according to sex in clinical trials. In 1993 once again the Food and Drug Administration issues the Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs , expressing the hope for the inclusion of women in the experimentation protocols so as to guarantee an equal representation. Along the same line are the International Ethical Guidelines for Biomedical Research Involving Human Subjects (1993, revised in 2002), which recommend researchers, sponsors and ethics committees to not exclude women of child bearing age from experimentation, not considering the potential of pregnancy a sufficient reason to limit their participation and recognising women the capacity to take a “rational decision” in taking part in research.

Wizemann and Pardue ( 2001 ); Mattison ( 2004 ), pp. 112–117.

Franconi et al. ( 2007 ), pp. 81–97.

This is the theory maintained by feminists. Cfr. DeBruin ( 1994 ), pp. 117–146; Sherwin ( 1994 ), pp. 533–538; Sherwin ( 1992 ), pp. 158–175; and Merton ( 1996 ).

On the topics see the Opinion of the National Ethics Council in Europe: Austrian Bioethics Commission at the Federal Chancellery ( 2009 ); Belgian Advisory Committee on Bioethics ( 2004 , 2015 ); European Medicines Agency (EMA) ( 2005 , 2005 ); Italian National Bioethics Committee ( 2008 ). In USA: Columbia University Institutional Review Board ( 2012 ); John Hopkins University Center for Communication Programs ( 2003 ); The American College of Obstetricians and Gynecologists ( 2015 ); The Society for Women’s Health Research – United States Food and Drugs Administration Office of Women’s Health ( 2011 ); U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Office of Research on Women’s Health ( 2011 ); U.S. Government Accountability Office ( 1992 ); U.S. Government Accountability Office ( 2001 ); U.S. Food and Drug Administration ( 1993 ); U.S. National Institute of Health ( 2001 ). In other countries and on international level: Health Canada ( 2013 ); International Conference on Harmonisation (ICH) ( 2004 ); World Health Organization (WHO) ( 1995 , 1998 , 2010 ).

CIOMS 2016, Commentary on Guideline 19.

On the topics see: French National Consultative Ethics Committee for Health and Life Sciences ( 2003 ); Italian Committee for Bioethics ( 2011 , 2017 ); European Group on Ethics in Science and New Technologies (EGE) ( 2003 ); Nuffield Council on Bioethics ( 2005 ); U.S. Food and Drug Administration ( 2013 , 2016 ); U.S. National Bioethics Advisory Commission ( 2001 ); U.S. National Institute of Health ( 2001 ); Marshall ( 2007 ); Neves ( 2009 ).

In the context of international guidelines the ethical criteria of experimentation with particular reference to developing Countries have been elaborated in International Ethical Guidelines for Biomedical Research Involving Human Subjects 2002, which updated the 1993 guidelines of the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization; Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, in its most recently developed form by the World Medical Association (adopted in 1964, revised in 1975, 1983, 1989, 1996, 2000 and 2008), Working Party for the Elaboration of Guides for Research Ethics Committee Members (CDBI, 2010 , Rev. 1. 2).

Italian Committee for Bioethics ( 1992a , b ).

See art. 37 of the Declaration of Helsinki (updated in October 2013) that provides for the possibility of “unproven interventions in clinical practice”. It allows the use, under the responsibility of the doctor and with the consent of the patient or his legal representative, of “an unproven intervention”, when there are no proven treatments or other known interventions have proved ineffective, and after seeking expert opinion on the subject. The doctor must be convinced that this drug could “constitute a hope to save the life, restore the physical integrity or alleviate the suffering of the patient”. The article adds that “this intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and made publicly available when appropriate”. In one of the many drafts of the Universal Declaration on Bioethics and Human Rights of UNESCO, art. 16 of Scientific and Rational Method , after pointing out that every decision and practice should be based on the best scientific information available, stressed that (v) “be considered individually, allowing for the possibility of exceptions to general rules and practices”. The article was then removed from the final version, but it is the sign of a debate within the international community itself.

‘Expanded access’ refers to treatment offered to patients in the absence of other effective treatment, emergency for individual and public health. Nevertheless, the spread of contagion cannot be sufficient to allow compassionate treatment only in these circumstances and thus result as being an advantage for these patients. If one considers the point of view of the person affected by a rare disease, with high mortality but not contagious, the lack of danger of its spread would paradoxically deprive these patients of an opportunity that others instead have in trying a treatment.

The expression “compassionate use” can be traced in art. 83 of EC Regulation no. 726/2004, that authorizes individual states to derogate from the Community rules for the marketing of drugs in the event that a group of patients with a chronic, seriously debilitating or life-threatening illness, cannot be treated satisfactorily with an authorized medicinal product. EC Regulation no. 726/2004 was amended by Regulation no. 1394/2007. The latter introduces for the first time the definition of “advanced therapies”, including not only gene therapy and somatic cell therapy, as well as tissue engineered products. The main innovations introduced by the Regulation include: the establishment of an expert committee (Committee for Advanced Therapies), within the European Medicines Agency (EMA); the adoption of new requirements for quality, safety and traceability of the donation, procurement and control; the adoption of new regulatory procedures for classification and certification; support for small and medium businesses with incentives to promote entrepreneurship. In addition, Regulation stipulates that each Member State should standardize the production and use of advanced therapies for individual patients, treated in national public facilities, and therefore not aimed at placing on the market and commercialization.

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Palazzani, L. (2019). Scientific Research and Experimenting on Human Beings. In: Innovation in Scientific Research and Emerging Technologies. Springer, Cham. https://doi.org/10.1007/978-3-030-16733-2_1

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Controversial New Guidelines Would Allow Experiments On More Mature Human Embryos

New guidance would ease restrictions on researching embryos in the lab. BSIP/Science Source hide caption

New guidance would ease restrictions on researching embryos in the lab.

For decades, scientists have been prohibited from keeping human embryos alive in their labs for more than 14 days. The prohibition was aimed at avoiding a thicket of ethical issues that would be raised by doing experiments on living human embryos as they continue to develop.

But on Wednesday, an influential scientific society recommended scrapping that blanket taboo, known as the "14-day rule." The International Society for Stem Cell Research released new guideline s that say it could be permissible to study living human embryos in the lab for longer than two weeks.

This guidance will now be considered by regulatory bodies in each country that conducts this type of research to decide what research will be permitted and how. Currently in the U.S., regulatory bodies at universities and other research institutions universally adhere to the 14-day rule. If the new guidance is adopted, it would be a major change.

"When you ask, 'Is this ethically bad?' Well, you also have to put the opposite: Are there ethical issues for not doing research in that period?" says Robin Lovell-Badge of the Crick Institute , who chaired the task force that wrote the guidelines. "In many ways, you could argue it would be unethical not to do it."

Studying embryos as they develop beyond 14 days could help scientists solve many medical problems, including infertility, miscarriages and birth defects, Lovell-Badge and others argue.

"There's very good reasons for doing this research. And people shouldn't be scared about it if there are robust mechanisms of review and oversight," Lovell-Badge says.

While many scientists and bioethicists are welcoming the new guidelines, others criticize them as being far too permissive.

"I think it's deeply troubling," says Dr. Daniel Sulmasy , a bioethicist at Georgetown University. "Now, any sign of respect for the human embryo is gone."

Others are especially concerned that the new guidelines include no clear stopping point for how long a developing embryo could be studied in a lab dish.

"If you don't have any endpoint, could you take embryos to 20 weeks? To 24 weeks? Is viability the only endpoint," asks Hank Greely, a Stanford University bioethicist who otherwise praises the new guidelines. "Is viability even an endpoint?"

Lovell-Badge defends the recommendations.

"I felt that it would be both difficult and a little pointless to propose any new limit, which would be arbitrary, much like 14 days," Lovell-Badge says.

The original cutoff was set at 14 days for a variety of reasons. For example, 14 days is around the time when an embryo starts to develop the first signs of a central nervous system. It's also when an embryo can no longer split into twins. At the time, scientists were far from being able to sustain living embryos in the lab anywhere close to 14 days.

But in recent years scientists have gradually extended how long they can sustain human embryos in lab dishes, increasing pressure from some researchers and bioethicists to revise the rule.

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Scientists create living entities in the lab that closely resemble human embryos.

At the same time, scientists developed the ability to create "embryoids," which are living entities made from human stem cells that have become increasingly complex and similar to human embryos. That added pressure to extend the rule so scientists could compare these new entities with naturally conceived embryos.

"That period of development between, say, 14 days, which is the current limit, and let's say 28 days, a huge amount is happening. It's a very critical period," Lovell-Badge says.

The guidelines stress such experiments should only be allowed after each country has a robust public debate and the public at large agrees that such research is acceptable. In addition, any experiments must be carefully monitored to make sure the research is absolutely necessary to learn something important, according to the guidelines.

"We're not saying it should now happen. We're saying it's possible for it to happen," Lovell-Badge says.

The guidelines could be especially influential in countries that do not have laws or regulations governing this kind of research.

In the U.S., the federal government is prohibited from funding for research involving human embryos. But that kind of research can be done with private money. And the National Institutes of Health has been waiting for the new guidelines to help decide whether to lift a moratorium on funding research involving chimera embryos.

"We are looking forward to reading the ISSCR guidelines," the NIH said in a statement to NPR. "ISSCR has long been a thoughtful voice for the international stem cell research community, and we will certainly think carefully about their report."

Martin Pera, a stem cell researcher at the Jackson Laboratory who was not involving in writing the guidelines, called them "responsible and well-considered" in an email to NPR. "Adoption of these guidelines by regulatory bodies will ensure that research that has wide-ranging potential to improve human health can proceed with appropriate ethical oversight."

The change in the 14-day rule is just one of a long list of sensitive lines of scientific research the new guidelines address, ranging from human cloning to gene-editing human embryos. Some research, such as human cloning and creating babies from gene-edited embryos, remains off-limits. But the guidelines generally take a more permissive stance, including opening the door to creating gene-edited babies someday if it would be safe and solve an important medical problem.

Scientists Create Early Embryos That Are Part Human, Part Monkey

The guidelines also detail rules that would allow researchers to create chimera embryos for research. These are embryos that are part human, part animal. They're made by injecting human stem cells into animal embryos. Scientists recently announced they had done this with monkey embryos .

The goal is to learn more about basic embryonic development and perhaps someday use these embryos to breed animals such as pigs and cows with human hearts, livers and kidneys for organ transplants. Those entities raise many difficult ethical questions. One concern is that the cells could end up in other parts of the animals' bodies, such as their brains.

"Surely there are some human-animal chimera experiments that are entirely permissible and good. But there are some that would be monstrous," wrote J. Benjamin Hurlbut, a Arizona State University bioethicist, in an email to NPR.

"Do we really need to hark back to Mary Shelley to remind ourselves that the production of monstrosity may well grow out of a misguided sense of the good — combined with the thrill of the power of control over life? What is at stake here if not that?" Hurlbut wrote.

To assuage such concerns, the guidelines recommend a variety of restrictions and steps that should be taken to prevent that from occurring.

"There is a way to genetically engineer both the embryo and the stem cells so that the stem cells will only make a particular organ," says Insoo Hyun, a bioethicist at Harvard and Case Western Reserve universities, who helped write the guidelines. "Nobody wants a chimeric embryo to grow into a part-human, part-animal thing that has human cells from head to toe mixed in."

But the guidelines could conceivably allow a human-monkey embryo to develop inside a monkey's womb. And so those requirements did little to satisfy critics.

"I think we have just not thought through the moral status of these novel beings," says Françoise Baylis, a bioethicist at Dalhousie University in Canada.

"I think a number of people would be, you know, rightfully concerned that, that there are very little constraints on what's happening with the human embryo."

Hurlbut, who called the new guidelines "breathtakingly expansive," agrees.

"What was ethically unthinkable just a few years ago is getting treated as not only permissible but even unproblematic now," Hurlbut says.

"Under these guidelines an oversight committee can deliberate behind closed doors and quietly give its blessing to scientists to impregnate a monkey with a partly human embryo, or to see how far into human development scientists can grow artificially constructed synthetic human embryos in bottles."

Others, however, praise the new guidelines.

"As this is a time of rapid advances in stem cell-based research, it is critical to have a set of guidelines that all researchers can refer to, regardless of the stage of their research," says Juan Carlos Izpisua Belmonte , a researcher at the Salk Institute, who created the part-human, part-monkey embryos.

• human embryos

August 7, 2019

Medicine in Space: What Microgravity Can Tell Us about Human Health

Astronaut Serena Auñón-Chancellor discusses her experience in microgravity and doing biological experiments in space

By Andrea Thompson

Serena Auñón-Chancellor mixes protein crystal samples to help scientists understand how they work. Proteins crystallized in microgravity are often higher in quality than those grown on Earth and present opportunities for the development of new drugs to treat disease.

Microgravity, or very weak gravity, on the International Space Station (ISS) is what lets astronauts glide and somersault around effortlessly as they orbit Earth. It is also a useful environment for gaining insights into human health, both in terms of the impacts of long-duration spaceflight and new perspectives on diseases that afflict people on our planet.

Space-based biomedical research was one of the key topics discussed last week at the ISS R&D Conference in Atlanta. Researchers highlighted some of the current work on the Space Station, as well as further studies NASA and the ISS National Laboratory hope to do while seeking to commercialize low-Earth orbit. They also aim to use the ISS as a stepping-stone to landing back on the Moon and eventually Mars.

As a physician certified in both internal and aerospace medicine, astronaut Serena Auñón-Chancellor has a keen interest in this work. She helped conduct several biomedical experiments as a flight engineer onboard the ISS for 197 days during Expeditions 56 and 57 in 2018, an experience she described to the audience at the conference. Scientific American sat down with Auñón-Chancellor to discuss the research she conducted and her own experiences with the impacts microgravity has on the human body.

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[ An edited transcript of the interview follows. ]

What effects of microgravity did you experience?

The experience is personal for everybody. This was my first flight. I’d learned for years about all the different things that happen to the body, but you don’t know, until you get up there, how you’re going to feel. So when I got up there—certainly, your stomach doesn’t feel great, the first few days. You just don’t feel like eating as much. You feel like everything’s floating inside. Turning your head quickly in one direction and then the other, there was a bit of a lag [for the brain to catch up]. But that diminishes so quickly that after about the first week, you start thinking, “Okay, I’m beginning to feel like I’m normal again.”

We all see changes in the immune system. We see what they call latent viral reactivation [when dormant viruses begin reproducing], and that’s measured in our saliva. We have almost everything sampled and tested up there, from feces to saliva to urine to blood. But it’s interesting how quickly things do revert almost back to normal once you get down to Earth.

What are some of the key questions about how microgravity impacts human health?

I think the biggest health challenges—certainly for exploration-class missions, longer and longer missions—number one is radiation. We’re pretty well protected on the ISS—the thick shielding of the vehicle, Earth’s magnetic field and the atmosphere all provide protection. Once you change that baseline standard—with a different vehicle, maybe thinner shielding, no atmosphere—your exposure is greater. And you’re at more risk for solar particle events on a long transit, let’s say to Mars.

Continuing bone loss is also a concern. How do we mitigate that? The exercise devices we have on the station are big. We love them, but can we take something that large on the next vehicle? Probably not. So we’re looking at devices to use on the vehicles that are going to take us farther out.

Then we have the effects on the eyes—the issues that we’ve seen with changes in the shape of the eyeball itself, swelling of the optic nerve, changes in vision. I did not experience any of those, but certainly, we’ve had other astronauts that have. So it’s something we’re tracking; we’re trying to figure out how to predict it and then how can we treat it if it does pop up.

Being a physician, it must have been interesting watching and comparing what happened to you versus your crewmates.

It’s kind of the old adage that until you walk in somebody’s shoes, you really have no idea. But then you realize, also, how different everybody’s bodies are. For example, it takes time to learn how to move gracefully in microgravity. I flew up there with Alex Gerst [of the European Space Agency], and this was his second long-duration flight. And when we first entered the ISS, I very clearly remember him saying, “Wow, my body remembers how to move up here.” His first flight was four years prior to that, but his brain had remembered. There was neural memory in there that said, “When you get up into microgravity, it’s a light touch here, a light foothold here. Just use your toe here to hold yourself down. Push off here, gently.” So he just remembered. To me, that tells you how remarkable the brain is at adapting to new environments.

What makes microgravity such a desirable place for conducting biological science?

Cell growth differs up in microgravity. Scientists are able to culture cells such as endothelial cells [which line the inside of blood and lymphatic vessels] for a little bit longer. They grow in a better, more three-dimensional fashion than growing them on a flat plate on Earth, which allows scientists to study different things.

The other thing that changes is that it’s sort of like a rapid aging process that occurs in orbit. So we look at all the molecular markers and the way cells also change in orbit. And processes that take years on the ground, such as osteoporosis, happen much more quickly up there. So scientists see it as a test bed.

And finally, the third thing that I really enjoyed looking at was protein crystal experiments. Whether it was a protein involved in Parkinson’s disease or a drug that a pharmaceutical company was studying to improve, these protein crystals are structures that grow better [on the ISS]. They grow in a more 3-D, better-ordered structure in orbit, because they’re not limited to that flat 2-D plate. There’s a lack of convective currents in microgravity, which helps those crystals grow. It gives scientists better insight into the protein structure. So if they were able to look at a protein that causes Parkinson’s disease and have 30 percent more insight, or even 20 percent more, they’re able to look at it and say, “Huh, we see a new target for an inhibitor drug” or “We can tweak our drug a little bit and reduce that side effect, because now we’re better able to look at this protein.”

Which medical experiments do you think are the most exciting?

Certainly, the Angiex chemotherapy study we did up there—I spent about six to eight weeks working on that. It was a good chunk of my time on the mission. The scientist was looking at: How did endothelial cells grow? And could we test chemotherapeutic agents on them? And what I want to know from the principle investigator is, “Did the ISS help you create a chemotherapy agent to target a tumor’s vascular supply?” Because that, to us, is important. Cancer is still, and has been for a long time, the emperor of all maladies. And so any small part that we can do to help in that fight, I’ll take it. Because a lot of my patients are dealing with cancer. Everybody’s dealt with cancer in some way, whether it’s a family member, a friend or themselves personally. This is something that everybody’s looking at and interested in solving. I’d love to see more studies like that.

Does your work in space inform how you relate to your patients on Earth?

I talk to my patients about the cancer research. I talk about Alzheimer’s disease a lot, because beta-amyloid protein is involved in many different disease processes. And I say, “Look, we’re getting better insight, through protein crystal growth, into beta-amyloid protein, which means that three to five years from now, we could potentially have better treatments out there.” And they love it hearing about it. They absolutely love it.

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Learn more about the ethics and policies that have had and effect on research conducted by the Public Health Ethics Program sponsored by Tuskegee University and CDC.

After the U.S Public Health Service's (USPHS) Untreated Syphilis Study at Tuskegee, the government changed its research practices.

In 1974, the National Research Act was signed into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The group identified basic principles of research conduct and suggested ways to ensure those principles were followed.

Regulations and standards

In addition to the Commission's recommendations, since 1974 researchers are required to get voluntary informed consent from all persons taking part in studies done or funded by the Department of Health, Education, and Welfare (DHEW). They also required that all DHEW-supported studies using human subjects be reviewed by Institutional Review Boards (IRBs). IRBs decide whether research protocols meet ethical standards.

The rules and policies for human subjects research have been reviewed and revised many times since they were first approved. Efforts to promote the highest ethical standards in research are ongoing.

Ethics Advisory Board and policies

An Ethics Advisory Board was formed in the late-1970s to review ethical issues of biomedical research. As a result, the 1979 publication known as The Belmont Report summarized the three ethical principles that should guide human research: respect for persons ; beneficence ; justice. From 1980-1983, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research reported "every two years on the adequacy and uniformity of the Federal rules and policies, and their implementation, for the protection of human subjects in biomedical and behavioral research." In 1991, federal departments and agencies (16 total) adopted the Federal Policy for the Protection of Human Subjects .

In October 1995, President Bill Clinton created a National Bioethics Advisory Commission, funded and led by the Department of Health and Human Services. The commission's task was to review current regulations, policies, and procedures. Also, to ensure all possible safeguards are in place to protect research volunteers. It was succeeded by the President's Council on Bioethics , which was established in 2001, and then the Presidential Commission for the Study of Bioethical Issues established in 2009.

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The Untreated Syphilis Study at Tuskegee was conducted between 1932 and 1972 to observe the natural history of untreated syphilis.

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• v.63(2 Suppl 3); 2022 Jun

Ethical considerations regarding animal experimentation

Aysha karim kiani.

1 Allama Iqbal Open University, Islamabad, Pakistan

2 MAGI EUREGIO, Bolzano, Italy

DEREK PHEBY

3 Society and Health, Buckinghamshire New University, High Wycombe, UK

GARY HENEHAN

4 School of Food Science and Environmental Health, Technological University of Dublin, Dublin, Ireland

RICHARD BROWN

5 Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada

PAUL SIEVING

6 Department of Ophthalmology, Center for Ocular Regenerative Therapy, School of Medicine, University of California at Davis, Sacramento, CA, USA

PETER SYKORA

7 Department of Philosophy and Applied Philosophy, University of St. Cyril and Methodius, Trnava, Slovakia

ROBERT MARKS

8 Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel

BENEDETTO FALSINI

9 Institute of Ophthalmology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy

NATALE CAPODICASA

10 MAGI BALKANS, Tirana, Albania

STANISLAV MIERTUS

11 Department of Biotechnology, University of SS. Cyril and Methodius, Trnava, Slovakia

12 International Centre for Applied Research and Sustainable Technology, Bratislava, Slovakia

LORENZO LORUSSO

13 UOC Neurology and Stroke Unit, ASST Lecco, Merate, Italy

DANIELE DONDOSSOLA

14 Center for Preclincal Research and General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca‘ Granda Ospedale Maggiore Policlinico, Milan, Italy

15 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

GIANLUCA MARTINO TARTAGLIA

16 Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy

17 UOC Maxillo-Facial Surgery and Dentistry, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy

MAHMUT CERKEZ ERGOREN

18 Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus

MUNIS DUNDAR

19 Department of Medical Genetics, Erciyes University Medical Faculty, Kayseri, Turkey

SANDRO MICHELINI

20 Vascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, Marino, Italy

DANIELE MALACARNE

21 MAGI’S LAB, Rovereto (TN), Italy

GABRIELE BONETTI

Astrit dautaj, kevin donato, maria chiara medori, tommaso beccari.

22 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

MICHELE SAMAJA

23 MAGI GROUP, San Felice del Benaco (BS), Italy

STEPHEN THADDEUS CONNELLY

24 San Francisco Veterans Affairs Health Care System, University of California, San Francisco, CA, USA

DONALD MARTIN

25 Univ. Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, SyNaBi, Grenoble, France

ASSUNTA MORRESI

26 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy

ARIOLA BACU

27 Department of Biotechnology, University of Tirana, Tirana, Albania

KAREN L. HERBST

28 Total Lipedema Care, Beverly Hills California and Tucson Arizona, USA

MYKHAYLO KAPUSTIN

29 Federation of the Jewish Communities of Slovakia

LIBORIO STUPPIA

30 Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, University "G. d'Annunzio", Chieti, Italy

LUDOVICA LUMER

31 Department of Anatomy and Developmental Biology, University College London, London, UK

GIAMPIETRO FARRONATO

Matteo bertelli.

32 MAGISNAT, Peachtree Corners (GA), USA

Animal experimentation is widely used around the world for the identification of the root causes of various diseases in humans and animals and for exploring treatment options. Among the several animal species, rats, mice and purpose-bred birds comprise almost 90% of the animals that are used for research purpose. However, growing awareness of the sentience of animals and their experience of pain and suffering has led to strong opposition to animal research among many scientists and the general public. In addition, the usefulness of extrapolating animal data to humans has been questioned. This has led to Ethical Committees’ adoption of the ‘four Rs’ principles (Reduction, Refinement, Replacement and Responsibility) as a guide when making decisions regarding animal experimentation. Some of the essential considerations for humane animal experimentation are presented in this review along with the requirement for investigator training. Due to the ethical issues surrounding the use of animals in experimentation, their use is declining in those research areas where alternative in vitro or in silico methods are available. However, so far it has not been possible to dispense with experimental animals completely and further research is needed to provide a road map to robust alternatives before their use can be fully discontinued.

How to cite this article: Kiani AK, Pheby D, Henehan G, Brown R, Sieving P, Sykora P, Marks R, Falsini B, Capodicasa N, Miertus S, Lorusso L, Dondossola D, Tartaglia GM, Ergoren MC, Dundar M, Michelini S, Malacarne D, Bonetti G, Dautaj A, Donato K, Medori MC, Beccari T, Samaja M, Connelly ST, Martin D, Morresi A, Bacu A, Herbst KL, Kapustin M, Stuppia L, Lumer L, Farronato G, Bertelli M. Ethical considerations regarding animal experimentation. J Prev Med Hyg 2022;63(suppl.3):E255-E266. https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2768

Introduction

Animal model-based research has been performed for a very long time. Ever since the 5 th century B.C., reports of experiments involving animals have been documented, but an increase in the frequency of their utilization has been observed since the 19 th century [ 1 ]. Most institutions for medical research around the world use non-human animals as experimental subjects [ 2 ]. Such animals might be used for research experimentations to gain a better understanding of human diseases or for exploring potential treatment options [ 2 ]. Even those animals that are evolutionarily quite distant from humans, such as Drosophila melanogaster , Zebrafish ( Danio rerio ) and Caenorhabditis elegans , share physiological and genetic similarities with human beings [ 2 ]; therefore animal experimentation can be of great help for the advancement of medical science [ 2 ].

For animal experimentation, the major assumption is that the animal research will be of benefit to humans. There are many reasons that highlight the significance of animal use in biomedical research. One of the major reasons is that animals and humans share the same biological processes. In addition, vertebrates have many anatomical similarities (all vertebrates have lungs, a heart, kidneys, liver and other organs) [ 3 ]. Therefore, these similarities make certain animals more suitable for experiments and for providing basic training to young researchers and students in different fields of biological and biomedical sciences [ 3 ]. Certain animals are susceptible to various health problems that are similar to human diseases such as diabetes, cancer and heart disease [ 4 ]. Furthermore, there are genetically modified animals that are used to obtain pathological phenotypes [ 5 ]. A significant benefit of animal experimentation is that test species can be chosen that have a much shorter life cycle than humans. Therefore, animal models can be studied throughout their life span and for several successive generations, an essential element for the understanding of disease progression along with its interaction with the whole organism throughout its lifetime [ 6 ].

Animal models often play a critical role in helping researchers who are exploring the efficacy and safety of potential medical treatments and drugs. They help to identify any dangerous or undesired side effects, such as birth defects, infertility, toxicity, liver damage or any potential carcinogenic effects [ 7 ]. Currently, U.S. Federal law, for example, requires that non-human animal research is used to demonstrate the efficacy and safety of any new treatment options before proceeding to trials on humans [ 8 ]. Of course, it is not only humans benefit from this research and testing, since many of the drugs and treatments that are developed for humans are routinely used in veterinary clinics, which help animals live longer and healthier lives [ 4 ].

COVID-19 AND THE NEED FOR ANIMAL MODELS

When COVID-19 struck, there was a desperate need for research on the disease, its effects on the brain and body and on the development of new treatments for patients with the disease. Early in the disease it was noticed that those with the disease suffered a loss of smell and taste, as well as neurological and psychiatric symptoms, some of which lasted long after the patients had “survived” the disease [ 9-15 ]. As soon as the pandemic started, there was a search for appropriate animal models in which to study this unknown disease [ 16 , 17 ]. While genetically modified mice and rats are the basic animal models for neurological and immunological research [ 18 , 19 ] the need to understand COVID-19 led to a range of animal models; from fruit flies [ 20 ] and Zebrafish [ 21 ] to large mammals [ 22 , 23 ] and primates [ 24 , 25 ]. And it was just not one animal model that was needed, but many, because different aspects of the disease are best studied in different animal models [ 16 , 25 , 26 ]. There is also a need to study the transmission pathways of the zoonosis: where does it come from, what are the animal hosts and how is it transferred to humans [ 27 ]?

There has been a need for animal models for understanding the pathophysiology of COVID-19 [ 28 ], for studying the mechanisms of transmission of the disease [ 16 ], for studying its neurobiology [ 29 , 30 ] and for developing new vaccines [ 31 ]. The sudden onset of the COVID-19 pandemic has highlighted the fact that animal research is necessary, and that the curtailment of such research has serious consequences for the health of both humans and animals, both wild and domestic [ 32 ] As highlighted by Adhikary et al. [ 22 ] and Genzel et al. [ 33 ] the coronavirus has made clear the necessity for animal research and the danger in surviving future such pandemics if animal research is not fully supported. Genzel et al. [ 33 ], in particular, take issue with the proposal for a European ban on animal testing. Finally, there is a danger in bypassing animal research in developing new vaccines for diseases such as COVID-19 [ 34 ]. The purpose of this paper is to show that, while animal research is necessary for the health of both humans and animals, there is a need to carry out such experimentation in a controlled and humane manner. The use of alternatives to animal research such as cultured human cells and computer modeling may be a useful adjunct to animal studies but will require that such methods are more readily accessible to researchers and are not a replacement for animal experimentation.

Pros and cons of animal experimentation

Arguments against animal experimentation.

A fundamental question surrounding this debate is to ask whether it is appropriate to use animals for medical research. Is our acceptance that animals have a morally lower value or standard of life just a case of speciesism [ 35 ]? Nowadays, most people agree that animals have a moral status and that needlessly hurting or abusing pets or other animals is unacceptable. This represents something of a change from the historical point of view where animals did not have any moral status and the treatment of animals was mostly subservient to maintaining the health and dignity of humans [ 36 ].

Animal rights advocates strongly argue that the moral status of non-human animals is similar to that of humans, and that animals are entitled to equality of treatment. In this view, animals should be treated with the same level of respect as humans, and no one should have the right to force them into any service or to kill them or use them for their own goals. One aspect of this argument claims that moral status depends upon the capacity to suffer or enjoy life [ 37 ].

In terms of suffering and the capacity of enjoying life, many animals are not very different from human beings, as they can feel pain and experience pleasure [ 38 ]. Hence, they should be given the same moral status as humans and deserve equivalent treatment. Supporters of this argument point out that according animals a lower moral status than humans is a type of prejudice known as “speciesism” [ 38 ]. Among humans, it is widely accepted that being a part of a specific race or of a specific gender does not provide the right to ascribe a lower moral status to the outsiders. Many advocates of animal rights deploy the same argument, that being human does not give us sufficient grounds declare animals as being morally less significant [ 36 ].

ARGUMENTS IN FAVOR OF ANIMAL EXPERIMENTATION

Those who support animal experimentation have frequently made the argument that animals cannot be elevated to be seen as morally equal to humans [ 39 ]. Their main argument is that the use of the terms “moral status” or “morality” is debatable. They emphasize that we must not make the error of defining a quality or capacity associated with an animal by using the same adjectives used for humans [ 39 ]. Since, for the most part, animals do not possess humans’ cognitive capabilities and lack full autonomy (animals do not appear to rationally pursue specific goals in life), it is argued that therefore, they cannot be included in the moral community [ 39 ]. It follows from this line of argument that, if animals do not possess the same rights as human beings, their use in research experimentation can be considered appropriate [ 40 ]. The European and the American legislation support this kind of approach as much as their welfare is respected.

Another aspect of this argument is that the benefits to human beings of animal experimentation compensate for the harm caused to animals by these experiments.

In other words, animal harm is morally insignificant compared to the potential benefits to humans. Essentially, supporters of animal experimentation claim that human beings have a higher moral status than animals and that animals lack certain fundamental rights accorded to humans. The potential violations of animal rights during animal research are, in this way, justified by the greater benefits to mankind [ 40 , 41 ]. A way to evaluate when the experiments are morally justified was published in 1986 by Bateson, which developed the Bateson’s Cube [ 42 ]. The Cube has three axes: suffering, certainty of benefit and quality of research. If the research is high-quality, beneficial, and not inflicting suffering, it will be acceptable. At the contrary, painful, low-quality research with lower likelihood of success will not be acceptable [ 42 , 43 ].

Impact of experimentations on animals

Ability to feel pain and distress.

Like humans, animal have certain physical as well as psychological characteristics that make their use for experimentation controversial [ 44 ].

In the last few decades, many studies have increased knowledge of animal awareness and sentience: they indicate that animals have greater potential to experience damage than previously appreciated and that current rights and protections need to be reconsidered [ 45 ]. In recent times, scientists as well as ethicists have broadly acknowledged that animals can also experience distress and pain [ 46 ]. Potential sources of such harm arising from their use in research include disease, basic physiological needs deprivation and invasive procedures [ 46 ]. Moreover, social deprivation and lack of the ability to carry out their natural behaviors are other causes of animal harm [ 46 ]. Several studies have shown that, even in response to very gentle handling and management, animals can show marked alterations in their physiological and hormonal stress markers [ 47 ].

In spite of the fact that suffering and pain are personalized experiences, several multi-disciplinary studies have provided clear evidence of animals experiencing pain and distress. In particular, some animal species have the ability to express pain similarly to human due to common psychological, neuroanatomical and genetic characteristics [ 48 ]. Similarly, animals share a resemblance to humans in their developmental, genetic and environmental risk factors for psychopathology. For instance, in many species, it has been shown that fear operates within a less organized subcortical neural circuit than pain [ 49 , 50 ]. Various types of depression and anxiety disorders like posttraumatic stress disorder have also been reported in mammals [ 51 ].

PSYCHOLOGICAL CAPABILITIES OF ANIMALS

Some researchers have suggested that besides their ability to experience physical and psychological pain and distress, some animals also exhibit empathy, self-awareness and language-like capabilities. They also demonstrate tools-linked cognizance, pleasure-seeking and advanced problem-solving skills [ 52 ]. Moreover, mammals and birds exhibit playful behavior, an indicator of the capacity to experience pleasure. Other taxa such as reptiles, cephalopods and fishes have also been observed to display playful behavior, therefore the current legislation prescribes the use of environmental enrichers [ 53 ]. The presence of self-awareness ability, as assessed by mirror self-recognition, has been reported in magpies, chimpanzees and other apes, and certain cetaceans [ 54 ]. Recently, another study has revealed that crows have the ability to create and use tools that involve episodic-like memory formation and its retrieval. From these findings, it may be suggested that crows as well as related species show evidence of flexible learning strategies, causal reasoning, prospection and imagination that are similar to behavior observed in great apes [ 55 ]. In the context of resolving the ethical dilemmas about animal experimentation, these observations serve to highlight the challenges involved [ 56 , 57 ].

Ethics, principles and legislation in animal experimentation

Ethics in animal experimentation.

Legislation around animal research is based on the idea of the moral acceptability of the proposed experiments under specific conditions [ 58 ]. The significance of research ethics that ensures proper treatment of experimental animals [ 58 ]. To avoid undue suffering of animals, it is important to follow ethical considerations during animal studies [ 1 ]. It is important to provide best human care to these animals from the ethical and scientific point of view [ 1 ]. Poor animal care can lead to experimental outcomes [ 1 ]. Thus, if experimental animals mistreated, the scientific knowledge and conclusions obtained from experiments may be compromised and may be difficult to replicate, a hallmark of scientific research [ 1 ]. At present, most ethical guidelines work on the assumption that animal experimentation is justified because of the significant potential benefits to human beings. These guidelines are often permissive of animal experimentation regardless of the damage to the animal as long as human benefits are achieved [ 59 ].

PRINCIPLE OF THE 4 RS

Although animal experimentation has resulted in many discoveries and helped in the understanding numerous aspects of biological science, its use in various sectors is strictly controlled. In practice, the proposed set of animal experiments is usually considered by a multidisciplinary Ethics Committee before work can commence [ 60 ]. This committee will review the research protocol and make a judgment as to its sustainability. National and international laws govern the utilization of animal experimentation during research and these laws are mostly based on the universal doctrine presented by Russell and Burch (1959) known as principle of the 3 Rs. The 3Rs referred to are Reduction, Refinement and Replacement, and are applied to protocols surrounding the use of animals in research. Some researchers have proposed another “R”, of responsibility for the experimental animal as well as for the social and scientific status of the animal experiments [ 61 ]. Thus, animal ethics committees commonly review research projects with reference to the 4 Rs principles [ 62 ].

The first “R”, Reduction means that the experimental design is examined to ensure that researchers have reduced the number of experimental animals in a research project to the minimum required for reliable data [ 59 ]. Methods used for this purpose include improved experimental design, extensive literature search to avoid duplication of experiments [ 35 ], use of advanced imaging techniques, sharing resources and data, and appropriate statistical data analysis that reduce the number of animals needed for statistically significant results [ 2 , 63 ].

The second “R”, Refinement involves improvements in procedure that minimize the harmful effects of the proposed experiments on the animals involved, such as reducing pain, distress and suffering in a manner that leads to a general improvement in animal welfare. This might include for example improved living conditions for research animals, proper training of people handling animals, application of anesthesia and analgesia when required and the need for euthanasia of the animals at the end of the experiment to curtail their suffering [ 63 ].

The third “R”, Replacement refers to approaches that replace or avoid the use of experimental animals altogether. These approaches involve use of in silico methods/computerized techniques/software and in vitro methods like cell and tissue culture testing, as well as relative replacement methods by use of invertebrates like nematode worms, fruit flies and microorganisms in place of vertebrates and higher animals [ 1 ]. Examples of proper application of these first “3R2 principles are the use of alternative sources of blood, the exploitation of commercially used animals for scientific research, a proper training without use of animals and the use of specimen from previous experiments for further researches [ 64-67 ].

The fourth “R”, Responsibility refers to concerns around promoting animal welfare by improvements in experimental animals’ social life, development of advanced scientific methods for objectively determining sentience, consciousness, experience of pain and intelligence in the animal kingdom, as well as effective involvement in the professionalization of the public discussion on animal ethics [ 68 ].

OTHER ASPECTS OF ANIMAL RESEARCH ETHICS

Other research ethics considerations include having a clear rationale and reasoning for the use of animals in a research project. Researchers must have reasonable expectation of generating useful data from the proposed experiment. Moreover, the research study should be designed in such a way that it should involve the lowest possible sample size of experimental animals while producing statistically significant results [ 35 ].

All individual researchers that handle experimental animals should be properly trained for handling the particular species involved in the research study. The animal’s pain, suffering and discomfort should be minimized [ 69 ]. Animals should be given proper anesthesia when required and surgical procedures should not be repeated on same animal whenever possible [ 69 ]. The procedure of humane handling and care of experimental animals should be explicitly detailed in the research study protocol. Moreover, whenever required, aseptic techniques should be properly followed [ 70 ]. During the research, anesthetization and surgical procedures on experimental animals should only be performed by professionally skilled individuals [ 69 ].

The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines that are issued by the National Center for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) are designed to improve the documentation surrounding research involving experimental animals [ 70 ]. The checklist provided includes the information required in the various sections of the manuscript i.e. study design, ethical statements, experimental procedures, experimental animals and their housing and husbandry, and more [ 70 ].

It is critical to follow the highest ethical standards while performing animal experiments. Indeed, most of the journals refuse to publish any research data that lack proper ethical considerations [ 35 ].

INVESTIGATORS’ ETHICS

Since animals have sensitivity level similar to the human beings in terms of pain, anguish, survival instinct and memory, it is the responsibility of the investigator to closely monitor the animals that are used and identify any sign of distress [ 71 ]. No justification can rationalize the absence of anesthesia or analgesia in animals that undergo invasive surgery during the research [ 72 ]. Investigators are also responsible for giving high-quality care to the experimental animals, including the supply of a nutritious diet, easy water access, prevention of and relief from any pain, disease and injury, and appropriate housing facilities for the animal species [ 73 ]. A research experiment is not permitted if the damage caused to the animal exceeds the value of knowledge gained by that experiment. No scientific advancement based on the destruction and sufferings of another living being could be justified. Besides ensuring the welfare of animals involved, investigators must also follow the applicable legislation [ 74 , 75 ].

To promote the comfort of experimental animals in England, an animal protection society named: ‘The Society for the Preservation of Cruelty to Animals’ (now the Royal Society for the Prevention of Cruelty to Animals) was established (1824) that aims to prevent cruelty to animal [ 76 ].

ANIMAL WELFARE LAWS

Legislation for animal protection during research has long been established. In 1876 the British Parliament sanctioned the ‘Cruelty to Animals Act’ for animal protection. Russell and Burch (1959) presented the ‘3 Rs’ principles: Replacement, Reduction and Refinement, for use of animals during research [ 61 ]. Almost seven years later, the U.S.A also adopted regulations for the protection of experimental animals by enacting the Laboratory Animal Welfare Act of 1966 [ 60 ]. In Brazil, the Arouca Law (Law No. 11,794/08) regulates the animal use in scientific research experiments [ 76 ].

These laws define the breeding conditions, and regulate the use of animals for scientific research and teaching purposes. Such legal provisions control the use of anesthesia, analgesia or sedation in experiments that could cause distress or pain to experimental animals [ 59 , 76 ]. These laws also stress the need for euthanasia when an experiment is finished, or even during the experiment if there is any intense suffering for the experimental animal [ 76 ].

Several national and international organizations have been established to develop alternative techniques so that animal experimentation can be avoided, such as the UK-based National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) ( www.caat.jhsph.edu ), the European Centre for the Validation of Alternative Methods (ECVAM) [ 77 ], the Universities Federation for Animal Welfare (UFAW) ( www.ufaw.org.uk ), The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) [ 78 ], and The Center for Alternatives to Animal Testing (CAAT) ( www.caat.jhsph.edu ). The Brazilian ‘Arouca Law’ also constitutes a milestone, as it has created the ‘National Council for the Control of Animal Experimentation’ (CONCEA) that deals with the legal and ethical issues related to the use of experimental animals during scientific research [ 76 ].

Although national as well as international laws and guidelines have provided basic protections for experimental animals, the current regulations have some significant discrepancies. In the U.S., the Animal Welfare Act excludes rats, mice and purpose-bred birds, even though these species comprise almost 90% of the animals that are used for research purpose [ 79 ]. On the other hand, certain cats and dogs are getting special attention along with extra protection. While the U.S. Animal Welfare Act ignores birds, mice and rats, the U.S. guidelines that control research performed using federal funding ensure protections for all vertebrates [ 79 , 80 ].

Living conditions of animals

Choice of the animal model.

Based on all the above laws and regulations and in line with the deliberations of ethical committees, every researcher must follow certain rules when dealing with animal models.

Before starting any experimental work, thorough research should be carried out during the study design phase so that the unnecessary use of experimental animals is avoided. Nevertheless, certain research studies may have compelling reasons for the use of animal models, such as the investigation of human diseases and toxicity tests. Moreover, animals are also widely used in the training of health professionals as well as in training doctors in surgical skills [ 1 , 81 ].

Researcher should be well aware of the specific traits of the animal species they intend to use in the experiment, such as its developmental stages, physiology, nutritional needs, reproductive characteristics and specific behaviors. Animal models should be selected on the basis of the study design and the biological relevance of the animal [ 1 ].

Typically, in early research, non-mammalian models are used to get rapid insights into research problems such as the identification of gene function or the recognition of novel therapeutic options. Thus, in biomedical and biological research, among the most commonly used model organisms are the Zebrafish, the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans . The main advantage of these non-mammalian animal models is their prolific reproducibility along with their much shorter generation time. They can be easily grown in any laboratory setting, are less expensive than the murine animal models and are somewhat more powerful than the tissue and cell culture approaches [ 82 ].

Caenorhabditis elegans is a small-sized nematode with a short life cycle and that exists in large populations and is relatively inexpensive to cultivate. Scientists have gathered extensive knowledge of the genomics and genetics of Caenorhabditis elegans ; but Caenorhabditis elegans models, while very useful in some respects, are unable to represent all signaling pathways found in humans. Furthermore, due to its short life cycle, scientists are unable to investigate long term effects of test compounds or to analyze primary versus secondary effects [ 6 ].

Similarly, the fruit fly Drosophila melanogaster has played a key role in numerous biomedical discoveries. It is small in size, has a short life cycle and large population size, is relatively inexpensive to breed, and extensive genomics and genetics information is available [ 6 ]. However, its respiratory, cardiovascular and nervous systems differ considerably from human beings. In addition, its immune system is less developed when compared to vertebrates, which is why effectiveness of a drug in Drosophila melanogaster may not be easily extrapolated to humans [ 83 ].

The Zebrafish ( Danio rerio ) is a small freshwater teleost, with transparent embryos, providing easy access for the observation of organogenesis and its manipulation. Therefore, Zebrafish embryos are considered good animal models for different human diseases like tuberculosis and fetal alcohol syndrome and are useful as neurodevelopmental research models. However, Zebrafish has very few mutant strains available, and its genome has numerous duplicate genes making it impossible to create knockout strains, since disrupting one copy of the gene will not disrupt the second copy of that gene. This feature limits the use of Zebrafish as animal models to study human diseases. Additionally they are rather expensive, have long life cycle, and genomics and genetics studies are still in progress [ 82 , 84 ].

Thus, experimentation on these three animals might not be equivalent to experimentation on mammals. Mammalian animal model are most similar to human beings, so targeted gene replacement is possible. Traditionally, mammals like monkey and mice have been the preferred animal models for biomedical research because of their evolutionary closeness to humans. Rodents, particularly mice and rats, are the most frequently used animal models for scientific research. Rats are the most suitable animal model for the study of obesity, shock, peritonitis, sepsis, cancer, intestinal operations, spleen, gastric ulcers, mononuclear phagocytic system, organ transplantations and wound healing. Mice are more suitable for studying burns, megacolon, shock, cancer, obesity, and sepsis as mentioned previously [ 85 ].

Similarly, pigs are mostly used for stomach, liver and transplantation studies, while rabbits are suitable for the study of immunology, inflammation, vascular biology, shock, colitis and transplantations. Thus, the choice of experimental animal mainly depends upon the field of scientific research under consideration [ 1 ].

HOUSING AND ENVIRONMENTAL ENRICHMENT

Researchers should be aware of the environment and conditions in which laboratory animals are kept during research, and they also need to be familiar with the metabolism of the animals kept in vivarium, since their metabolism can easily be altered by different factors such as pain, stress, confinement, lack of sunlight, etc. Housing conditions alter animal behavior, and this can in turn affect experimental results. By contrast, handling procedures that feature environmental enrichment and enhancement help to decrease stress and positively affect the welfare of the animals and the reliability of research data [ 74 , 75 ].

In animals, distress- and agony-causing factors should be controlled or eliminated to overcome any interference with data collection as well as with interpretation of the results, since impaired animal welfare leads to more animal usage during experiment, decreased reliability and increased discrepancies in results along with the unnecessary consumption of animal lives [ 86 ].

To reduce the variation or discrepancies in experimental data caused by various environmental factors, experimental animals must be kept in an appropriate and safe place. In addition, it is necessary to keep all variables like humidity, airflow and temperature at levels suitable for those species, as any abrupt variation in these factors could cause stress, reduced resistance and increased susceptibility to infections [ 74 ].

The space allotted to experimental animals should permit them free movement, proper sleep and where feasible allow for interaction with other animals of the same species. Mice and rats are quite sociable animals and must, therefore, be housed in groups for the expression of their normal behavior. Usually, laboratory cages are not appropriate for the behavioral needs of the animals. Therefore, environmental enrichment is an important feature for the expression of their natural behavior that will subsequently affect their defense mechanisms and physiology [ 87 ].

The features of environmental enrichment must satisfy the animals’ sense of curiosity, offer them fun activities, and also permit them to fulfill their behavioral and physiological needs. These needs include exploring, hiding, building nests and gnawing. For this purpose, different things can be used in their environment, such as PVC tubes, cardboard, igloos, paper towel, cotton, disposable masks and paper strips [ 87 ].

The environment used for housing of animals must be continuously controlled by appropriate disinfection, hygiene protocols, sterilization and sanitation processes. These steps lead to a reduction in the occurrence of various infectious agents that often found in vivarium, such as Sendai virus, cestoda and Mycoplasma pulmonis [ 88 ].

Euthanasia is a term derived from Greek, and it means a death without any suffering. According to the Brazilian Arouca Law (Article 14, Chapter IV, Paragraphs 1 and 2), an animal should undergo euthanasia, in strict compliance with the requirements of each species, when the experiment ends or during any phase of the experiment, wherever this procedure is recommended and/or whenever serious suffering occurs. If the animal does not undergo euthanasia after the intervention it may leave the vivarium and be assigned to suitable people or to the animal protection bodies, duly legalized [ 1 ].

Euthanasia procedures must result in instant loss of consciousness which leads to respiratory or cardiac arrest as well as to complete brain function impairment. Another important aspect of this procedure is calm handling of the animal while taking it out of its enclosure, to reduce its distress, suffering, anxiety and fear. In every research project, the study design should include the details of the appropriate endpoints of these experimental animals, and also the methods that will be adopted. It is important to determine the appropriate method of euthanasia for the animal being used. Another important point is that, after completing the euthanasia procedure, the animal’s death should be absolutely confirmed before discarding their bodies [ 87 , 89 ].

Relevance of animal experimentations and possible alternatives

Relevance of animal experiments and their adverse effects on human health.

One important concern is whether human diseases, when inflicted on experimental animals, adequately mimic the progressions of the disease and the treatment responses observed in humans. Several research articles have made comparisons between human and animal data, and indicated that the results of animals’ research could not always be reliably replicated in clinical research among humans. The latest systematic reviews about the treatment of different clinical conditions including neurology, vascular diseases and others, have established that the results of animal studies cannot properly predict human outcomes [ 59 , 90 ].

At present, the reliability of animal experiments for extrapolation to human health is questionable. Harmful effects may occur in humans because of misleading results from research conducted on animals. For instance, during the late fifties, a sedative drug, thalidomide, was prescribed for pregnant women, but some of the women using that drug gave birth to babies lacking limbs or with foreshortened limbs, a condition called phocomelia. When thalidomide had been tested on almost all animal models such as rats, mice, rabbits, dogs, cats, hamsters, armadillos, ferrets, swine, guinea pig, etc., this teratogenic effect was observed only occasionally [ 91 ]. Similarly, in 2006, the compound TGN 1412 was designed as an immunomodulatory drug, but when it was injected into six human volunteer, serious adverse reactions were observed resulting from a deadly cytokine storm that in turn led to disastrous systemic organ failure. TGN 1412 had been tested successfully in rats, mice, rabbits, and non-human primates [ 92 ]. Moreover, Bailey (2008) reported 90 HIV vaccines that had successful trial results in animals but which failed in human beings [ 93 ]. Moreover, in Parkinson disease, many therapeutic options that have shown promising results in rats and non-human primate models have proved harmful in humans. Hence, to analyze the relevance of animal research to human health, the efficacy of animal experimentation should be examined systematically [ 94 , 95 ]. At the same time, the development of hyperoxaluria and renal failure (up to dialysis) after ileal-jejunal bypass was unexpected because this procedure was not preliminarily evaluated on an animal model [ 96 ].

Several factors play a role in the extrapolation of animal-derived data to humans, such as environmental conditions and physiological parameters related to stress, age of the experimental animals, etc. These factors could switch on or off genes in the animal models that are specific to species and/or strains. All these observations challenge the reliability and suitability of animal experimentation as well as its objectives with respect to human health [ 76 , 92 ].

ALTERNATIVE TO ANIMAL EXPERIMENTATION/DEVELOPMENT OF NEW PRODUCTS AND TECHNIQUES TO AVOID ANIMAL SACRIFICE IN RESEARCH

Certainly, in vivo animal experimentation has significantly contributed to the development of biological and biomedical research. However it has the limitations of strict ethical issues and high production cost. Some scientists consider animal testing an ineffective and immoral practice and therefore prefer alternative techniques to be used instead of animal experimentation. These alternative methods involve in vitro experiments and ex vivo models like cell and tissue cultures, use of plants and vegetables, non-invasive human clinical studies, use of corpses for studies, use of microorganisms or other simpler organism like shrimps and water flea larvae, physicochemical techniques, educational software, computer simulations, mathematical models and nanotechnology [ 97 ]. These methods and techniques are cost-effective and could efficiently replace animal models. They could therefore, contribute to animal welfare and to the development of new therapies that can identify the therapeutics and related complications at an early stage [ 1 ].

The National Research Council (UK) suggested a shift from the animal models toward computational models, as well as high-content and high-throughput in vitro methods. Their reports highlighted that these alternative methods could produce predictive data more affordably, accurately and quickly than the traditional in vivo or experimental animal methods [ 98 ].

Increasingly, scientists and the review boards have to assess whether addressing a research question using the applied techniques of advanced genetics, molecular, computational and cell biology, and biochemistry could be used to replace animal experiments [ 59 ]. It must be remembered that each alternative method must be first validated and then registered in dedicated databases.

An additional relevant concern is how precisely animal data can mirror relevant epigenetic changes and human genetic variability. Langley and his colleagues have highlighted some of the examples of existing and some emerging non-animal based research methods in the advanced fields of neurology, orthodontics, infectious diseases, immunology, endocrine, pulmonology, obstetrics, metabolism and cardiology [ 99 ].

IN SILICO SIMULATIONS AND INFORMATICS

Several computer models have been built to study cardiovascular risk and atherosclerotic plaque build-up, to model human metabolism, to evaluate drug toxicity and to address other questions that were previously approached by testing in animals [ 100 ].

Computer simulations can potentially decrease the number of experiments required for a research project, however simulations cannot completely replace laboratory experiments. Unfortunately, not all the principles regulating biological systems are known, and computer simulation provide only an estimation of possible effects due to the limitations of computer models in comparison with complex human tissues. However, simulation and bio-informatics are now considered essential in all fields of science for their efficiency in using the existing knowledge for further experimental designs [ 76 ].

At present, biological macromolecules are regularly simulated at various levels of detail, to predict their response and behavior under certain physical conditions, chemical exposures and stimulations. Computational and bioinformatic simulations have significantly reduced the number of animals sacrificed during drug discovery by short listing potential candidate molecules for a drug. Likewise, computer simulations have decreased the number of animal experiments required in other areas of biological science by efficiently using the existing knowledge. Moreover, the development of high definition 3D computer models for anatomy with enhanced level of detail, it may make it possible to reduce or eliminate the need for animal dissection during teaching [ 101 , 102 ].

3D CELL-CULTURE MODELS AND ORGANS-ON-CHIPS

In the current scenario of rapid advancement in the life sciences, certain tissue models can be built using 3D cell culture technology. Indeed, there are some organs on micro-scale chip models used for mimicking the human body environment. 3D models of multiple organ systems such as heart, liver, skin, muscle, testis, brain, gut, bone marrow, lungs and kidney, in addition to individual organs, have been created in microfluidic channels, re-creating the physiological chemical and physical microenvironments of the body [ 103 ]. These emerging techniques, such as the biomedical/biological microelectromechanical system (Bio-MEMS) or lab-on-a-chip (LOC) and micro total analysis systems (lTAS) will, in the future, be a useful substitute for animal experimentation in commercial laboratories in the biotechnology, environmental safety, chemistry and pharmaceutical industries. For 3D cell culture modeling, cells are grown in 3D spheroids or aggregates with the help of a scaffold or matrix, or sometimes using a scaffold-free method. The 3D cell culture modeling conditions can be altered to add proteins and other factors that are found in a tumor microenvironment, for example, or in particular tissues. These matrices contain extracellular matrix components such as proteins, glycoconjugates and glycosaminoglycans that allow for cell communication, cell to cell contact and the activation of signaling pathways in such a way that the morphological and functional differentiation of these cells can accurately mimic their environment in vivo . This methodology, in time, will bridge the gap between in vivo and in vitro drug screening, decreasing the utilization of animal models during research [ 104 ].

ALTERNATIVES TO MICROBIAL CULTURE MEDIA AND SERUM-FREE ANIMAL CELL CULTURES

There are moves to reduce the use of animal derived products in many areas of biotechnology. Microbial culture media peptones are mostly made by the proteolysis of farmed animal meat. However, nowadays, various suppliers provide peptones extracted from yeast and plants. Although the costs of these plant-extracted peptones are the same as those of animal peptones, plant peptones are more environmentally favorable since less plant material and water are required for them to grow, compared with the food grain and fodder needed for cattle that are slaughtered for animal peptone production [ 105 ].

Human cell culture is often carried out in a medium that contains fetal calf serum, the production of which involves animal (cow) sacrifice or suffering. In fact, living pregnant cows are used and their fetuses removed to harvest the serum from the fetal blood. Fetal calf serum is used because it is a natural medium rich in all the required nutrients and significantly increases the chances of successful cell growth in culture. Scientists are striving to identify the factors and nutrients required for the growth of various types of cells, with a view to eliminating the use of calf serum. At present, most cell lines could be cultured in a chemically-synthesized medium without using animal products. Furthermore, data from chemically-synthesized media experiments may have better reproducibility than those using animal serum media, since the composition of animal serum does change from batch to batch on the basis of animals’ gender, age, health and genetic background [ 76 ].

ALTERNATIVES TO ANIMAL-DERIVED ANTIBODIES

Animal friendly affinity reagents may act as an alternative to antibodies produced, thereby removing the need for animal immunization. Typically, these antibodies are obtained in vitro by yeast, phage or ribosome display. In a recent review, a comparative analysis between animal friendly affinity reagents and animal derived-antibodies showed that the affinity reagents have superior quality, are relatively less time consuming, have more reproducibility and are more reliable and are cost-effective [ 106 , 107 ].

Conclusions

Animal experimentation led to great advancement in biological and biomedical sciences and contributed to the discovery of many drugs and treatment options. However, such experimentation may cause harm, pain and distress to the animals involved. Therefore, to perform animal experimentations, certain ethical rules and laws must be strictly followed and there should be proper justification for using animals in research projects. Furthermore, during animal experimentation the 4 Rs principles of reduction, refinement, replacement and responsibility must be followed by the researchers. Moreover, before beginning a research project, experiments should be thoroughly planned and well-designed, and should avoid unnecessary use of animals. The reliability and reproducibility of animal experiments should also be considered. Whenever possible, alternative methods to animal experimentation should be adopted, such as in vitro experimentation, cadaveric studies, and computer simulations.

While much progress has been made on reducing animal experimentation there is a need for greater awareness of alternatives to animal experiments among scientists and easier access to advanced modeling technologies. Greater research is needed to define a roadmap that will lead to the elimination of all unnecessary animal experimentation and provide a framework for adoption of reliable alternative methodologies in biomedical research.

Acknowledgements

This research was funded by the Provincia Autonoma di Bolzano in the framework of LP 15/2020 (dgp 3174/2021).

Conflicts of interest statement

Authors declare no conflict of interest.

Author's contributions

MB: study conception, editing and critical revision of the manuscript; AKK, DP, GH, RB, Paul S, Peter S, RM, BF, NC, SM, LL, DD, GMT, MCE, MD, SM, Daniele M, GB, AD, KD, MCM, TB, MS, STC, Donald M, AM, AB, KLH, MK, LS, LL, GF: literature search, editing and critical revision of the manuscript. All authors have read and approved the final manuscript.

Contributor Information

INTERNATIONAL BIOETHICS STUDY GROUP : Derek Pheby , Gary Henehan , Richard Brown , Paul Sieving , Peter Sykora , Robert Marks , Benedetto Falsini , Natale Capodicasa , Stanislav Miertus , Lorenzo Lorusso , Gianluca Martino Tartaglia , Mahmut Cerkez Ergoren , Munis Dundar , Sandro Michelini , Daniele Malacarne , Tommaso Beccari , Michele Samaja , Matteo Bertelli , Donald Martin , Assunta Morresi , Ariola Bacu , Karen L. Herbst , Mykhaylo Kapustin , Liborio Stuppia , Ludovica Lumer , and Giampietro Farronato