"The Warmth of His Continuing Interest": Henry K. Beecher, the Bioethics Revolution, and Pharmaceutical Industry Funding of Academic Medical Science in Cold War America.

This paper examines anesthesiologist Henry K. Beecher's funding relationship with pharmaceutical manufacturer Edward Mallinckrodt, Jr. Beecher is a familiar figure to both medical ethicists and historians of medicine for his role in the bioethics revolution of the 1960s and 1970s. In particular, his 1966 article "Ethics and Clinical Research" is widely considered a turning point in the post-World War II debate about informed consent. We argue that Beecher's scientific interests should be understood in the context of his funding relationship with Mallinckrodt and that this relationship shaped the direction of his work in important ways. We also argue that Beecher's views on research ethics reflected his assumption that collaboration with industry was a normal part of how academic science is conducted. In the conclusion of the paper we suggest that Beecher's failure to consider his relationship with Mallinckrodt as worthy of ethical deliberation has important lessons for academic researchers who collaborate with industry today.

[The genesis of informed consent in the context of medical research ethics 1900-1931]. / Die Genese des Informed Consent im Kontext der medizinischen Forschungsethik 1900­1931.

At the turn of the 20th century, the problem of human experimentation and the need to obtain consent became more important among medical practitioners and the general public. The case of the venereologist Albert Neisser, among others, is used to trace the development of research ethics standards in Germany between the end of the 19th century and 1931. The concept of informed consent, which originated in research ethics, is also of central importance in clinical ethics today.

The Dangers of White Supremacy: Nazi Sterilization and Its Mixed-Race Adolescent Victims.

Mixed-race African German and Vietnamese German children were born around 1921, when troops drawn from the French colonial empire occupied the Rhineland. These children were forcibly sterilized in 1937. Racial anthropologists had denounced them as "Rhineland Bastards," collected details on them, and persuaded the Nazi public health authorities to sterilize 385 of them. One of the adolescents later gave public interviews about his experiences. Apart from Hans Hauck, very few are known by name, and little is known about how their sterilization affected their lives. None of the 385 received compensation from the German state, either as victims of coerced sterilization or as victims of Nazi medical research. The concerned human geneticists went unprosecuted. (Am J Public Health. 2022;112(2):248-254. https://doi.org/10.2105/AJPH.2021.306593).

Experimental human hookworm infection: a narrative historical review.

In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy.

Human Infection Challenge Experiments: Then and Now.

In the midst of the Covid-19 pandemic, ethicists, researchers, and journalists have recommended studies that deliberately infect healthy volunteers with the coronavirus as a scientific means of expediting vaccine development. In this essay, we trace the history of infection challenge experiments and reflect on the Nuremberg Code of 1947, issued in response to brutal human experiments conducted by Nazi investigators in concentration camps. We argue that the Code continues to offer valuable guidance for assessing the ethics of this controversial form of research, with respect particularly to the acceptable limits to research risks and the social value of research necessary to justify exposing human participants to these risks.

Research on Tuberculosis in Nazi Germany and the Cruelest Medical Experiments on Jewish Children: An Observational Review.

BACKGROUND: Germany was a scientifically advanced country in the 19th and early 20th centuries, particularly in medicine, with a major interest in research and the treatment of tuberculosis. From 1933 until 1945, Nazi Germany perverted scientific research through criminal experimentations on captured prisoners of war and on "subhumans" by scientifically untrained, but politically driven, staff. This article exposes a series of failed experiments on tuberculosis in adults, experiments without scientific validity. Nonetheless, Dr. Kurt Heißmeyer repeated the experiment on Jewish children, who were murdered for the sake of personal academic ambition. It is now 75 years since liberation and the murdered children must be remembered. This observational review raises questions of medical and ethical values.

["Hypnotics" in the metropolis: Africans in the Colonial Hospital of Lisbon during the early twentieth century]. / "Hipnóticos" na metrópole: africanos no Hospital Colonial de Lisboa nas primeiras décadas do século XX.

At the start of the twentieth century, some Portuguese physicians traveled to Africa to study sleeping sickness (African trypanosomiasis). One was Ayres Kopke, a member of the first medical mission to Portuguese West Africa and professor at the School of Tropical Medicine. After returning to Lisbon, Kopke continued his research, which included observation of patients brought to the metropolis. Starting in 1903, health departments in the colonies were responsible for sending patients with certain exotic diseases to the Colonial Hospital of Lisbon. Based on documents from this hospital including photographs of patients (who at that time were called "hypnotics"), this article discusses the importance of human experiments in Lisbon for advances in tropical medicine during the colonial period.

No início do século XX, alguns médicos portugueses foram à África estudar a chamada doença do sono. Entre eles estava Ayres Kopke, membro da primeira missão médica à África Ocidental Portuguesa. De regresso a Lisboa, o professor da Escola de Medicina Tropical continuou suas pesquisas, inclusive por meio da observação de doentes trazidos para a metrópole. Desde 1903, as repartições de saúde nas colônias estavam incumbidas de enviar doentes com determinadas patologias exóticas para o Hospital Colonial de Lisboa. Com base em documentos desse hospital, incluindo fotografias dos doentes, então chamados de hipnóticos, o artigo aborda a importância das experiências com humanos na metrópole para o avanço da medicina tropical durante o colonialismo.

"Hipnóticos" na metrópole: africanos no Hospital Colonial de Lisboa nas primeiras décadas do século XX / "Hypnotics" in the metropolis: Africans in the Colonial Hospital of Lisbon during the early twentieth century

Resumo No início do século XX, alguns médicos portugueses foram à África estudar a chamada doença do sono. Entre eles estava Ayres Kopke, membro da primeira missão médica à África Ocidental Portuguesa. De regresso a Lisboa, o professor da Escola de Medicina Tropical continuou suas pesquisas, inclusive por meio da observação de doentes trazidos para a metrópole. Desde 1903, as repartições de saúde nas colônias estavam incumbidas de enviar doentes com determinadas patologias exóticas para o Hospital Colonial de Lisboa. Com base em documentos desse hospital, incluindo fotografias dos doentes, então chamados de hipnóticos, o artigo aborda a importância das experiências com humanos na metrópole para o avanço da medicina tropical durante o colonialismo.

Abstract At the start of the twentieth century, some Portuguese physicians traveled to Africa to study sleeping sickness (African trypanosomiasis). One was Ayres Kopke, a member of the first medical mission to Portuguese West Africa and professor at the School of Tropical Medicine. After returning to Lisbon, Kopke continued his research, which included observation of patients brought to the metropolis. Starting in 1903, health departments in the colonies were responsible for sending patients with certain exotic diseases to the Colonial Hospital of Lisbon. Based on documents from this hospital including photographs of patients (who at that time were called "hypnotics"), this article discusses the importance of human experiments in Lisbon for advances in tropical medicine during the colonial period.

Nazi Dentists on Trial: On the Political Complicity of a Long-Neglected Professional Community.

Studies on the complicity of the medical profession in the crimes of the Third Reich are on the rise. This also applies to the question of the extent to which doctors were brought to justice in international trials after World War II. This topic, however, has hardly been considered-let alone systematically investigated-with respect to German dentists. It is precisely this gap that this article will address. First, we quantitatively identify all dentists who were brought to justice in the post-war period. Second, we give a profile of this group. We focus on the following questions: Who among the group was brought to trial, and when? What crimes were they accused of, which sentences were handed down, and how did these sentences affect their future lives? Our study is based primarily on archival sources, which we analyzed with respect to the relevant secondary literature. Contrary to the widely-held assumption that dentists had almost never had been made to stand trial after the end of the war, we identified 48 dentists who were accused in court. The prototypical accused dentist was male, lived in a traditional family model, belonged to the National Socialist Workers' Party (NSDAP) and the Waffen-SS (Schutzstaffel), and was part of the so-called Kriegsjugendgeneration. The most frequent allegations made against these men were the theft of dental gold of murdered Nazi victims, an accusation unique to dentists; (accessory to) murder or manslaughter; and involvement in the deadly selections made in the concentration camps. In total, eight dentists were executed. Generally speaking, the earlier these proceedings and the sentencing took place, the harsher the sentence was. Many of those who received prison sentences subsequently found their way back into the dental profession.

Leo Fabian: A Life of Accomplishment.

Leo Fabian played a role in many anesthesia firsts: the first halothane anesthetics in the United States, the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. As was common for men of his generation, Fabian's first taste of medicine came during World War II, as a pharmacist's mate aboard the U.S.S. Bountiful. Afterward, he pursued his medical education before joining Dr. C. Ronald Stephen and the anesthesiology department at Duke. There he helped to create one of the first inhalers for halothane, the Fabian Newton Stephen (F-N-S) Fluothane Vaporizer. Fabian left Duke for the University of Mississippi Medical Center, where he consistently worked with the chair of surgery, Dr. James Hardy. Together they performed the first American electrical anesthetic, the first lung allotransplant, and the first heart xenotransplant. By the end of his time at Mississippi, Fabian and Hardy had several philosophical disagreements, and Fabian ultimately left for Washington University in St. Louis, where he rejoined Dr. Stephen. He served as Stephen's right-hand man and would oversee the department when Stephen was away. Fabian spent the final years of his career as chair of the department before his own health forced him to step down.

Biomedical Research in Times of Emergency: Lessons From History.

Coronavirus disease 2019 (COVID-19) has sickened millions, killed hundreds of thousands, and utterly disrupted the daily lives of billions of people around the world. In an effort to ameliorate this devastation, the biomedical research complex has allocated billions of dollars and scientists have initiated hundreds of clinical trials in an expedited effort to understand, prevent, and treat this disease. National emergencies can stimulate significant investment of financial, physical, and intellectual resources that catalyze impressive scientific accomplishments, as evident with the Manhattan Project, penicillin, and the polio vaccines in the 20th century. However, pressurized research has also led to false promises, disastrous consequences, and breaches in ethics. Antiserum in the 1918 flu epidemic, contaminated yellow fever vaccines in World War II, and unethical human experimentation with mustard gas offer just a few cautionary exemplars. It is critical to continue biomedical research efforts to address this pandemic, and it is appropriate that they receive priority in both attention and funding. But history also demonstrates the importance of treating early results-such as those associated with hydroxychloroquine-with caution as we only begin to understand the biology, epidemiology, and potential target points of COVID-19.

The Eye Color Experiment: From Berlin to Auschwitz and Back.

BACKGROUND: In an effort to alter eye color during World War II, devout Nazi researcher Karin Magnussen had adrenaline eye drops administered to inmates at the concentration camp Auschwitz-Birkenau. A Sinti family, with a high prevalence of heterochromia iridis, was forced to participate in this study. Members of this family, as well as other victims, were later killed and had their eyes enucleated and sent to Magnussen for examination. Magnussen articulated the findings of these events in a manuscript that has never been published. The author is the first ophthalmologist to review this manuscript. The generation who experienced the atrocities of World War II will soon be gone and awareness of what happened during this tragic chapter of world history is fading. OBJECTIVES: To describe these events to raise awareness among future generations. METHODS: A literature review and archival search was conducted. RESULTS: Magnussen's research was based on an animal study published in 1937. For Magnussen's study, adrenaline drops were administered to inmates, including a 12-year-old girl from the Sinti family. As there was a reported case of deaf-mutism within the family, Waardenburg syndrome seems to be the most plausible explanation for this family's heritable heterochromia. CONCLUSIONS: The effort to change eye color was doomed to fail from the beginning because there was a probable diagnosis of Waardenburg syndrome. Extinction of humans for ophthalmological research is an insane act beyond imagination. For the sake of these victims, and for the generations who still feel their pain, it is imperative to tell their stories.

"A Revolution in Favor of Reproduction"? Gynecology and Obstetrics in the "Third Reich".

During the "Third Reich," the majority of German gynecologists and obstetricians did not hesitate to put themselves at the service of those in power. In 1933, many gynecologists initially only focused on the fact that the biopolitical objectives of the National Socialists matched their own long-standing demands for population policy measures and the early detection and prevention of cancer. In addition, cooperating with the Nazis promised the political advancement of the profession, personal advantages, and the honorary title of Volksgesundheitsführer (national health leaders). As a result, gynecologists exchanged resources with the regime and thus contributed significantly to the implementation of the criminal racial policies of the Nazis. At the congresses of the Deutsche Gesellschaft für Gynäkologie (German Society of Gynecology) "non-Aryan" members, mostly of Jewish descent, were excluded, the law on forced sterilization of 1933 (Gesetz zur Verhütung erbkranken Nachwuchses/Law for the Prevention of Offspring with Hereditary Diseases) was scientifically legitimized, its implementation was propagated, and relevant surgical techniques were discussed with regard to their "certainty of success." In the course of these forced sterilizations, existing pregnancies were also terminated and the victims were misused for illegal scientific examinations or experiments. Drawing upon racial and utilitarian considerations, gynecologists did not even shy away from carrying out late abortions on forced laborers from the East during the Second World War, which were strictly prohibited even under the laws of the time. Some gynecologists carried out cruel experiments on humans in concentration camps, which primarily served their own careers and the biopolitical goals of those in power. The few times gynecologists did protest or resist was when the very interests of their profession seemed threatened, as in the dispute over home births and the rights of midwives. Social gynecological initiatives from the Weimar Republic, which were mainly supported and carried out by gynecologists persecuted for their Jewish descent since 1933, were either converted into National Socialist "education programs" or simply came to an end due to the exclusion of their initiators. German gynecologists had hoped for a large-scale promotion of the early detection of malignant diseases of the uterus and breasts, to which they had already made important contributions since the beginning of the 20th century. But even though the fight against cancer was allegedly one of the priorities of the Nazis, no comprehensive measures were taken. Still, a few locally limited initiatives to this end proved to be successful until well into the Second World War. In addition, German gynecologists established the modern concept of prenatal care and continued to advance endocrinological research and sterility therapy. After the end of the Nazi dictatorship, the historical guilt piled up during this period was suppressed and denied for decades. Its revision and processing only began in the 1990s.

Electroconvulsive Therapy in the Shadow of the Gas Chambers: Medical Innovation and Human Experimentation in Auschwitz.

Six years after it was first introduced into psychiatry in 1938, electroconvulsive therapy (ECT) became the subject of criminal human experiments in Nazi Germany. In 1944, at the Auschwitz III / Monowitz camp hospital, the Polish Jewish prisoner psychiatrist Zenon Drohocki started experimental treatments on prisoners with an ECT device that he had constructed himself. According to eyewitnesses, Drohocki's intention to treat mentally unstable prisoners was soon turned into something much more nefarious by SS doctors (including Josef Mengele), who used the device for deadly experiments. This article provides an account of this important and little-known aspect of the early history of ECT, drawing on an extensive array of historical literature, testimonies, and newly accessible documents. The adoption of ECT in Auschwitz is a prime example of the "grey zone" in which prisoner doctors had to operate-they could only survive as long as the SS considered their work useful for their own destructive purposes.

Belmont in Context.

Given its outsized influence as a core document in bioethics, it is worth reminding ourselves of the historical context in which the Belmont Report came to be. This article examines the societal forces that helped bring about the Belmont Report and that shaped its conception of ethical research. A product of a public investigation that included many nonscientists and espoused philosophical principles, the Report internalized a growing call in the late 1960s for oversight over the research enterprise, which had long been the private realm of physician-investigators. Belmont helped bring about a regulatory and oversight apparatus to the research enterprise, as well as a language and discipline of bioethics that added a multidisciplinary set of voices and decision-makers to discussions of what constitutes ethical research. Because it reflected the spirit of protectionism engendered by events of the 1960s and 1970s, Belmont also helped emphasize the importance of informed consent and the protection of vulnerable populations. But because the Report was a product of its time, contingent on historical developments and highly publicized events, it is not necessarily responsive to new factors that now condition the research enterprise.

The Origins and Drafting of the Belmont Report.

This article describes the origins and drafting of the Belmont Report by members of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

Belmont in Europe: A Mostly Indirect Influence.

This paper traces the reception of the Belmont Report in Europe and its influence on the development of European research ethics thinking and European research ethics systems. It is very difficult to trace a clear, linear reception history because it is difficult to disentangle the influence of the Report from the influence of concurrent developments, such as the 1975 revision of the World Medical Association Declaration of Helsinki and the requirement for research ethics review in the Vancouver Group's 1978 "Uniform Requirements for Manuscript Submission." The Report's insistence that the focus of research ethics should be the rights and interests of the individual research subject, and the use of an ethical framework and not ethical theory as the basis of analysis and justification of recommendations, were nevertheless very important for the development of research ethics. The divergence between Europe and the US in the governance of non-biomedical research can at least partly be explained by the absence of strong drivers for the introduction of research ethics committees outside of biomedicine in Europe, and by the ability of non-biomedical researchers to mobilize effectively against the introduction of such committees.

The Belmont Report and Innovative Practice.

One of the Belmont Report's most important contributions was the clear and serviceable distinction it drew between standard medical practice and biomedical research. A less well-known achievement of the Report was its conceptualization of innovative practice, a type of medical practice that is often mistaken for research because it is new, untested, or experimental. Although the discussion of innovative practice in Belmont is brief and somewhat cryptic, this does not reflect the significant progress its authors made in understanding innovative practice and the distinctive ethical issues it raises. This article explores the history and broader context of Belmont's conception of innovative practice, its strengths and weaknesses, and its contemporary relevance for scholars working in bioethics and health policy. While this conception of innovative practice deserves our attention, it is inherently limited in some important ways.

Experimental infections in humans-historical and ethical reflections.

Vaccine efficacy and prophylactic treatment of infections are tested best when the vaccinated or treated individual is challenged through deliberate infection with the respective pathogen. However, this trial design calls for particular ethical caution. Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse. We briefly introduce historical aspects of experimental infections in humans and the ethical debate around them and give estimates of the numbers of volunteers participating in human experimental infection models. Challenge models can offer a great chance and benefit for the development of medical interventions to fight infectious diseases, but only when they are appropriately controlled and regulated.

L'efficacité des vaccins et le traitement prophylactique des infections sont mieux testés lorsque l'individu vacciné ou traité est exposé par le biais d'une infection délibérée par l'agent pathogène concerné. Cependant, cette conception d'essai appelle à une prudence éthique particulière. Il est indispensable de connaître l'histoire des essais cliniques, y compris des essais qui se sont avérés problématiques ou même liés à des abus. Nous présentons brièvement les aspects historiques des infections expérimentales chez l'homme et le débat éthique autour d'eux et donnons des estimations du nombre de volontaires participant à des modèles d'infection expérimentale humaine. Les modèles d'exposition peuvent offrir une grande chance et un avantage pour le développement d'interventions médicales pour lutter contre les maladies infectieuses, mais uniquement lorsqu'elles sont contrôlées et réglementées de manière appropriée.