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Reflections on experimentation in medicine

Open AccessPublished:April 05, 2022DOI:https://doi.org/10.1016/j.ejim.2022.03.028

      Keywords

      Introduction

      Empirical medicine – over centuries - has been based on close observation of the patient`s history and the sick body. Thus, the ancient Greeks had already concepts of human anatomy, organ functions and their disorders - some of them still valid. Many of these ideas – partly preserved in the Oriental and Arabic culture - were introduced to the first medieval universities in Italy and Spain, where they became interwoven with Christian thinking [
      • Lafont O.
      Greek science in the centre of the dialogue between orient and occident.
      ]. Medicine was connected to spirituality, in an attempt of human beings to cope with illness, plagues and premature death. At the same time, empirical folk medicine persisted, based on trial and error [
      • Jankrift KP.
      Krankheiten und heilkunde im mittelalter.
      ]. With the Renaissance medicine approached our current understanding of human pathology through systematic anatomical examination, and the discovery of the circulatory system by William Harvey [
      • Silverman MA.
      De motu cordis: the Lumleian lecture of 1616.
      ], and through the introduction of the microscope in the late 17th century [
      • Ribatti D.
      An historical note on the cell theory.
      ].
      In the 19th century, modern and efficient medicine appeared on the horizon. It was based on the invention of anesthesia, asepsis and the first discoveries of disease causing microorganisms [
      • Fleming A.
      Louis Pasteur.
      ,
      • Koch R.
      Die atiologie der tuberculose.
      ]. The bloodletting, drawn from the theory of the humors, used as a panacea for treatment over millennia had come to an end. Systematic experiments were introduced. This included animals and humans, also self-experimentation - a topic beyond these reflections (Table 1). The driving force was not only the wish to cure, but also to satisfy curiosity, to understand.
      Table 1Examples for treatment and prevention of diseases.
      MeasureTime of introductionExamples of successRole of experimentation
      SurgeryCenturies ago, with major success since end of 19th centuryCancer treatment, joint replacement, organ transplantationTests on individual people, animal experiments
      VaccinationAround 1800, systematically 20th centuryEradication of smallpox and almost complete elimination of polio or tetanusTests on on individual people, animal and in-vitro experiments, phase I to IV trials
      Hormone therapyFirst half 20th centuryTherapy of diabetes, contraceptionAnimal and in-vitro experiments, tests on individual people
      AntibioticsMidth 20th centuryCure of bacterial infectionsIn-vitro and animal experiments, phase I to IV trials
      Antiviral drugsSecond half 20th centurySuppression HIV or HBV replication, cure of HCV infection
      HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.
      In-vitro studies and phase I to IV trials
      Gene therapy/silencing/editingBeginning 21th centuryFirst evidence of potential in hemophilia, amyloidosis or porphyriaIn-vitro and animal experiments, tests on individual people
      a HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.

      Experimentation and nature

      Humans have been victims of uncountable effects of the natural environment, some of which cause molecular and cellular damage, inducing diseases and eventual death. Certain genetic disorders are more or less random variants leading to a malfunctioning phenotype, a vagary of chance where teleologists might see an aim.
      Infections and their sequels can be regarded as another experiment of nature, a scourge of humankind from the very beginning. Now, more and more, the man-made environment interacts with soil, water, vegetation, weather, animals and microorganisms, often a protection against diseases, but harboring new menaces. This situation together with socio-economic behavior can lead to new types of genetic and infectious diseases, such as HIV infection or COVID-19.

      Experimentation, structures and society

      As medical doctors, we can well imagine the situation observed by Ignaz Semmelweis around 1850 in two obstetric departments in Vienna [
      • Semmelweis I.
      The etiology, concept, and prophylaxis of childbed fever.
      ]. The medical students rather than the midwives caused many unwanted and unforeseen deaths of the women in childbirth by transmitting the germs of childbed fever from the dead bodies in the newly established pathology department to the obstetrics. It took some time until Semmelweis had correctly analyzed the error of this catastrophic structural decision. However, it was ignored by his medical colleagues.
      History is full of examples of such unwanted social experiments. Some have a large dimension. Take air pollution. In some cities, it causes 20 and 40% of all deaths due to stroke, chronic obstructive pulmonary disease, lung cancer or ischemic heart disease [
      • Linou N.
      • Beagley J.
      • Huikuri S.
      • Renshaw N.
      Air pollution moves up the global health agenda.
      ]. Another example is obesity induced by a considerable decline of physical activity - facilitated by transport systems, working habits and increased consumption of cheap hyper palatable ultra-processed foods [
      • Popkin B.M.
      • Corvalan C.
      • Grummer-Strawn LM.
      Dynamics of the double burden of malnutrition and the changing nutrition reality.
      ], the latter strongly driven by the interests of the food industry. Often, decades will pass before we realize the price we pay for such unwitting social experiments, actually introduced to improve the quality of live. Then it is often difficult to steer the sluggish and complex social tanker on a different course. And socially tolerated drugs, such as alcohol and tobacco, are insufficiently touched under the primacy of the market.

      Experimentation and totalitarianism

      Robert L Berger, a well-known Hungarian-American surgeon specialized in cardiology and pulmonology, as a teenager himself a victim of the cruelty of German occupation in Hungary [
      • Yalom ID.
      Becoming myself: a psychiatrists memoir.
      ], dissects the brutal crime of the Dachau hypothermia study on civilian prisoners with respect to its scientific content [
      • Berger RL.
      Nazi science - the Dachau hypothermia experiments.
      ]. He demonstrates its critical shortcomings, lack of orderly protocols, inadequate methods or data falsification. Human experiments during Germany's Third Reich serve as an example of how the goals of a totalitarian society with their superimposed ideology suppress compassion and neglect responsive scientific behavior, mirroring the ideological madness some dutiful and well meaning academics can succumb to.

      Experimentation and disease prevention

      Based on anecdotal reports, Edward Jenner in 1796 took pustule material from cow-pox lesions and showed that inoculation of such material offered protection from small-pox [
      • Rusnock AA.
      Historical context and the roots of Jenner's discovery.
      ]. This was real progress compared to the rather dangerous and at that time already established variolation (inoculation with smallpox itself for prevention). A worldwide distribution of lymph from cow-pox disease followed – with excellent protective power [
      • Damaso CR.
      Revisiting Jenner's mysteries, the role of the Beaugency lymph in the evolutionary path of ancient smallpox vaccines.
      ]. In 1979, the WHO declared the disease eradicated. But stocks of the variola virus persist, at least in two specialized laboratories.
      With Jenner´s success in mind, the principle was transferred rather uncritically to the prevention of other diseases. The famous Albert Neisser (1855-1916), who identified the causative agent of gonorrhea, injected cell-free serum from patients with syphilis into young prostitutes in order to protect them. Yet, they developed syphilis. He himself openly described his experiments inciting a violent reaction and regulations for experimentation from the public [
      • Neisser A.
      Was wissen wir von einer serumtherapie bei syphilis und was haben wir von ihr zu erhoffen?.
      ]. The knowledge about the pathogen and its pathophysiology was not available to perform a preventive intervention that makes sense from today's point of view - apart from the lack of clear guidelines for human trials (Fig. 1).
      Fig 1
      Fig. 1Patient with congenital syphilis in 1920. This is an example of how the linkage of sociobiological behavior and infection determine the unwanted fate of an offspring. An experiment of nature that man could escape through the application of penicillin 30 years later.
      The COVID-19
      COVID-19: Coronavirus disease 2019.
      pandemic shows how these problems remain as we debate different vaccine approaches, assessment of their safety as well as technical aspects and efficacy when initiating application in humans. But it also shows which enormous scientific progress we have made to counter pandemic infections.
      The most recent experiment in a barely conceivable dimension is germline editing to prevent the sequels of genetic diseases, now at the threshold to reality - a new Pandora´s box to be opened [
      • Cyranoski D.
      CRISPR-baby scientist fails to satisfy critics.
      ].

      Experimentation and the understanding of disease

      Johannes Peter Müller (1801–1858) and Claude Bernard (1813–1878) were among the most prominent early physiologists in the first half of the 19th century. Von Müller had emphasized that “Nature … gives a suffering answer “ when manipulated. “Nothing is more difficult than to interpret it ” he continues [
      • Müller J.
      • Meyer-Abich A.
      Von dem bedürfnis der physiologie nach einer philosophischen naturbetrachtung (1824/1826).
      ].
      And Claude Bernard concurred: “The art of investigation is the cornerstone of all the experimental sciences. If the facts used as a basis for reasoning are ill-established or erroneous, everything will crumble or be falsified” [
      • Bernard C.
      An introduction to the study of experimental medicine.
      ]. For this, they started animal experiments as mainstay in research. Meanwhile, many different and refined models, e.g. knock-out and transgenic mice, have been developed to mimic human disease. However, translation remains a problem. To this end, tools to more closely approach the human situation have been developed, such as organoids.

      Experimentation and the treatment of disease

      Claude Bernhard stated “It is our duty and our right to perform an experiment on man whenever it can save his life, cure him or gain him some personal benefit… No surgeon is stopped by the most moving cries and sobs, because he sees only his idea and the purpose of his operation” [
      • Bernard C.
      An introduction to the study of experimental medicine.
      ]. This tendency persists to date, but fortunately “cries and sobs” can largely be abolished by anesthesia. Thus, in their need and desire to help, physicians have always been observers and experimenters, often as the same person.
      A less spectacular experiment is the administration of drugs. How can humans achieve and assess a valid outcome from such an intervention? This question was already well analyzed by Ludwig Büchner (1824–1899), brother of the famous German dramatist Georg Büchner (1813–1837). Ludwig Büchner writes about the therapeutic experiment: “There is only one condition in our power - the drug… butit lacks …accuracy”, and he continues, “Success is no evidence of truth because it can also depend on a number of other circumstances or events that we do not know…”, and, “Only very large numbers, ... with the correct composition and correct observation, can be valid here” [
      • Büchner L.
      Das therapeutische experiment.
      ]. It has taken several decades to meet these requirements. From the first half of the 20th century onwards, clinical trials, a new category of experiment, have been developed. One of the first randomized trials was performed to prove streptomycin as an effective drug for tuberculosis [
      • Marshall G.
      • Blacklock J.W.S.
      • Cameron C.
      • Capon N.B.
      • Cruickshank R.
      • Gaddum J.H.
      • et al.
      Streptomycin treatment of pulmonary tuberculosis.
      ]. Later, blinding and placebo were introduced to control for bias, the core of evidence-based medicine.

      Experimentation and systems biology

      There is an exponential publication of new findings in natural and life sciences. It includes more and more unbiased approaches – not linked to hypotheses - in the fields of genomics, proteomics, metabolomics or microbiomics, which can be associated with astounding amounts of social data. Here, the question arises as to whether the mere classical experiment has become outdated. Probably not. Even if computerized data analysis, including self-learning artificial intelligence, allows us to understand interaction and behavior of systems and their changing dependency, distinct hypotheses will continue to emerge [
      • Obermeyer Z.
      • Emanuel EJ.
      Predicting the future - big data, machine learning, and clinical medicine.
      ,
      • Tavassoly I.
      • Goldfarb J.
      • Iyengar R.
      • Kolch W.
      • Fey D.
      • Ryan C.J.
      Systems biology primer: the basic methods and approaches.
      ]. One may delegate the crucial steps of observation, comparison and judgment to machines, but still emerging hypotheses will have to be tested in a careful, unbiased manner.

      Experimentation and its acceptance in society

      When exposed to medical experiments, very sick humans become dependent, whereas sufficiently healthy, they can make their own decisions, provided freedom and correctly prepared information are available. Having made a decision, all they can do, is to trust in the skill and knowledge of the physician. However, the trustworthiness of science and medical behavior has always been threatened. Right or wrong is endangered by individual motives of the players in the realm of welfare. Today, individual recommendations of the physicians, based on their current knowledge and skill, are often challenged by the struggle between the social systems offering the means, the scientific associations with their interpretation of new findings and developments, and the opinions of various lay persons. Under these circumstances, the patients might question their doctors and the doctors might question their own judgment. Thus, a consensus on what is best for the patient may be more difficult to achieve, but in the end may be more robust. The experiment in its varied forms – crucial for the progress of medicine and its blessings - is embedded in these complex circumstances. In enlightened societies, there is a balance between freedom of development and protection of humans, which, however, can never be taken for granted.
      Can we be content in looking back? More yes than no. Humankind will always be exposed to the experiment of nature, the human component of which is constantly growing. Due to considerably enhanced insights, the possibilities to prevent and to tackle many diseases have enormously improved. Here, as a bioethical guide, the declaration of Helsinki is a simple and suitable blueprint
      https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct2008.pdf
      . From there more detailed statements may be deduced. But we still have to intensify our regular checks. And we cannot abstain from quick and efficient health care policy measures – always in an open dialogue with science, free markets and the people. Since the speed and complexity of this process are constantly increasing many resources are tied up by this.
      Nevertheless, dangers of totalitarianism persist [
      • Arendt H.
      The origins of totalitarianism: penguin classics.
      ]. Totalitarian regimes may have the advantage to enforce necessary decisions. However, in the end, the increasing complexity of our civilization can only be addressed by multifaceted societies with a globalized, free and flexible collective intelligence allowing timely self-correction. But even these systems do not escape the “Zeitgeist”. “Every period has its own sum total of errors and of truths” as Claude Bernhard puts it [
      • Bernard C.
      An introduction to the study of experimental medicine.
      ].
      Due to preventive and therapeutic experiments, we have achieved a lot when looking back. Regarding clinical trials, we have established wise and thorough regulations with respect to transparency, planning, patient care, documentation, data collection, data analysis and publication
      https://www.ich.org/page/process-harmonisation
      . However, there is room for improvement. The current gold standard of double-blind placebo controlled trial is the best method to reduce the potential for bias, while for patients and doctors, it is difficult to accept that the dice should decide on who receives treatment or placebo. And yet, the praised “real world data” as a contrast to randomized trials are nothing other than a complex network of individual decisions, which are quite often experimental.
      There would be no randomization to prove protection by parachutes [
      • Potts M.
      • Prata N.
      • Walsh J.
      • Grossman A.
      Parachute approach to evidence based medicine.
      ]. But we still need better definitions and consensus, when the parachute approach is to be preferred over randomization. The possibility to collect, analyze and compare extensive amounts of data should allow assessment of safety, efficacy and life quality as valid evidence without randomized trials being necessary - at least in some situations (Table 2).
      Table 2Tasks for the future.
      Regular review of control mechanisms in the use of experiments in medicine.
      Review of statements in social media.
      Definition of situations in which randomized controlled trials are necessary or not necessary to demonstrate the effect of a new medical intervention.
      Definition of the role of artificial intelligence in experimentation and medicine.
      Besides the gold standard of randomized trials to prove new medical interventions, societies are increasingly developing further mechanisms to assess the degree of benefit of a new drug or technology to counter profit-driven interests of the pharmaceutical or medical technology industry.

      Experimentation and emotional attitude of physicians and patients

      Emotional attitude is not directly addressed in the different oaths, although emotions, such as empathy, compassion or sympathy – the definitions of which overlap and which are entangled - are crucial behaviors towards a patient in certain situations. Interpretation of the motives underlying the doctor´s emphatic behavior is secondary in this context. What counts is to provide help for patients in their distress. But empathic feeling is of a spotlight nature. The patient should know that there is a trustworthy engagement over a longer period, beyond the instantaneous reaction.
      Unfortunately, a responsible, fact-based process is being contaminated by some of the untrustworthy emotional statements made on social media, some of which are gaining enormous popularity.
      As nature, the physician, who in the end is part of nature, may be emotionally detached towards the patient when performing experiments, in a persistent desire to understand, to find a form of “truth”, to detect the unknown. This can be interwoven with other motives, such as the longing for public attention and recognition. In this process, empathy should not be disregarded - acting as a brake to dehumanization. However, we must not assume that sentiments can replace unperturbed objectiveness necessary to protect human dignity and health.

      Acknowledgment

      The author thanks Alan Hofmann for his generosity and his advice, Heinz Schott for discussion, Dieter Lütjohann for help in formatting the manuscript, and the referees for their suggestions.

      References

        • Lafont O.
        Greek science in the centre of the dialogue between orient and occident.
        Rev Hist Pharm. 2016; 64 (Paris): 503-518
        • Jankrift KP.
        Krankheiten und heilkunde im mittelalter.
        Wissenschafl Buchgesell, Darmstadt2003
        • Silverman MA.
        De motu cordis: the Lumleian lecture of 1616.
        J R Soc Med. 2007; 100: 199-204
        • Ribatti D.
        An historical note on the cell theory.
        Exp Cell Res. 2018; 364: 1-4
        • Fleming A.
        Louis Pasteur.
        Br Med J 1.4502. 1947; 1: 521-522
        • Koch R.
        Die atiologie der tuberculose.
        Berl Klin Wochenschr. 1882; 15: 428-445
        • Semmelweis I.
        The etiology, concept, and prophylaxis of childbed fever.
        Madison: The University of Wisconsin Press, 1983
        • Linou N.
        • Beagley J.
        • Huikuri S.
        • Renshaw N.
        Air pollution moves up the global health agenda.
        BMJ. 2018; 363: k4933
        • Popkin B.M.
        • Corvalan C.
        • Grummer-Strawn LM.
        Dynamics of the double burden of malnutrition and the changing nutrition reality.
        Lancet. 2020; 395: 65-74
        • Yalom ID.
        Becoming myself: a psychiatrists memoir.
        Basic Books, New York2017
        • Berger RL.
        Nazi science - the Dachau hypothermia experiments.
        N Engl J Med. 1990; 322: 1435-1440
        • Rusnock AA.
        Historical context and the roots of Jenner's discovery.
        Hum Vaccines Immunother. 2016; 12: 2025-2028
        • Damaso CR.
        Revisiting Jenner's mysteries, the role of the Beaugency lymph in the evolutionary path of ancient smallpox vaccines.
        Lancet Infec Dis. 2018; 18: E55-E63
        • Neisser A.
        Was wissen wir von einer serumtherapie bei syphilis und was haben wir von ihr zu erhoffen?.
        Arch Dermat. 1898; 44: 431-539
        • Cyranoski D.
        CRISPR-baby scientist fails to satisfy critics.
        Nature. 2018; 564: 13-14
        • Müller J.
        • Meyer-Abich A.
        Von dem bedürfnis der physiologie nach einer philosophischen naturbetrachtung (1824/1826).
        (editor)Biologie der goethezeit. Hippokrates-Verlag Marquardt & Cie., Stuttgart1949: 256-281
        • Bernard C.
        An introduction to the study of experimental medicine.
        2nd ed. Henry Schuman, New York1949
        • Büchner L.
        Das therapeutische experiment.
        Arch Pathol Anat. 1854; 6: 271-309
        • Marshall G.
        • Blacklock J.W.S.
        • Cameron C.
        • Capon N.B.
        • Cruickshank R.
        • Gaddum J.H.
        • et al.
        Streptomycin treatment of pulmonary tuberculosis.
        Br Med J. 1948; 2: 769-782
        • Obermeyer Z.
        • Emanuel EJ.
        Predicting the future - big data, machine learning, and clinical medicine.
        N Engl J of Med. 2016; 375: 1216-1219
        • Tavassoly I.
        • Goldfarb J.
        • Iyengar R.
        • Kolch W.
        • Fey D.
        • Ryan C.J.
        Systems biology primer: the basic methods and approaches.
        (editors)Systems biology. Portland Press Ltd, London2018: 487-500
        • Arendt H.
        The origins of totalitarianism: penguin classics.
        2017
        • Potts M.
        • Prata N.
        • Walsh J.
        • Grossman A.
        Parachute approach to evidence based medicine.
        Br Med J. 2006; 333: 701-703