Today, the name Johann Christian Reil is perhaps best known to neuroanatomists and those working in mental health for this German physician, who was born over 250 years ago, made seminal contributions to both these fields. As his legacy, we have several structures in the brain that bear his name as well as ‘psychiatry’, a specialty that he named. However, earlier in his career, Reil was responsible for another, perhaps even more generally applicable piece of work, when he set forth the principles on which the modern evaluation of drugs in humans should be based.
Born in Northwest Germany, Reil began his medical education in Göttingen in 1779. He taught at the University of Halle for 22 years, during which time he established himself as an esteemed physician, scientist and educator. During his tenure, he promoted the idea that medical practice should be grounded in physiology, which in turn should have chemistry as its foundation.
In 1810, he moved to the new Berlin University as the Dean of the Medical Faculty, but the continued political unrest in Europe would interrupt his career and bring it to an end . In 1813, during the Napoleonic Wars, Reil volunteered for military service in the Prussian Army. He was commissioned to the field and, possibly as a result of his efforts to control a typhus epidemic then raging in Germany, he contracted the disease himself. Approximately 10% of the German population were infected and of these 10% (some 250,000) died. Reil was one of these unfortunates, dying of the disease at the age of 54.
His approach to pharmacology
In 1799, while he was the Professor of Medicine at Halle, Reil published his Beitrag zu den Prinzipien für jede künftige Pharmakologie (Contribution to the principles of a future pharmacology), in which he proposed a set of rules for the conduct of pharmacological research. These were presented as a theoretical framework on which to build a scientific approach to the study and evaluation of drugs.
As his first rule, Reil chooses to emphasise the overall approach and motivation for pharmacological research and indeed for any form of scientific endeavour.
1) The observer must have good common sense, good understanding, judgement, know how to make observations but also have a healthy degree of scepticism. He should not allow himself to be influenced by egotism, doctrine, an attachment to his school, or any prejudice, but by the simple love of truth.
Next, he states the importance of standardization both with respect to the drug under test and to the research participants. He notes that the researcher has the power to control the quality and consistency of drugs used, but the inter and intra-individual variation of human subjects can only be acknowledged and taken into account.
2) If the results of experiments, that is the changes brought about in the human body by the drugs, are consistent, they can be considered to be undoubtedly valid only if both the drugs and the human beings used in the series of tests are of a standardized nature. If the reagents which are working on one another are sometimes of one quality, sometimes of another, then the results will be correspondingly inconsistent…Every individual is different from another, and the same individual is not the same all of the time. With human beings a standard, average type has to be established, and before the experiment the test subjects must be assessed to identify exactly how they deviate from the standard so that variations in the results can be compensated for accurately for each individual according to how they deviated from the norm. How difficult this point is and yet how inexact efforts are with regard to it.
His third rule focuses on a similar theme, but here he discusses the importance of accurate diagnosis and previews one of his later themes—the all-importance of consistent nomenclature.
3) If we are experimenting on invalids the same things apply. Their illness must not be hypothetical, but real, identifiable from recognizable symptoms and deemed by the experimenter as really being present…How many mistakes have wormed their way into pharmacology because of confused terms about the nature of diseases and an imperfect semiotic of the same.
The reproducibility of research findings is emphasized in Reil’s fourth rule. The confounding effects of variables that have not been controlled and the cherry-picking of the desired result from a variety of non-standardised experiments are, in Reil’s opinion, reasons for the mistaken advocacy of ineffective treatments.
4) The experiments must be repeated often and under exactly the same conditions and in each repetition the results have to be the same. This alone can convince us that the results are effects of the drug. If, after one or more tests, a given effect sometimes is seen and sometimes not, the possibility remains that it was due not to the use of the drug but some other possible cause.
As an extension to his call for the control of variables within an experiment, Reil makes a call for the study of individual, or simple, drugs in his fifth rule. Here, he draws an important distinction between the study of drugs and their practical use, with his realization that compounds or mixtures will be prescribed. He argues, however, for their components to be tested first separately, and only when understood to be tested in combinations.
5) A drug must be tested on its own, not in conjunction with others, because otherwise it remains uncertain which of the substances used has brought about the effect in question. I am not suggesting, however, that in practice no compound substances should be used… First of all, we must determine the powers of the simple, individual substances in order to be able to work out the effect of compounds of them. The compounded substance must then be thoroughly tested, the same as for a simple, to understand the alteration of its effect which has been caused by its compounding.
The terminology we use to describe drug actions is called into question by Reil in his sixth rule. Here, he calls for specificity and a greater depth to our language that goes beyond mere superficial description.
6) The effects of drugs must be described specifically, not in terms that are too general, as otherwise they are of no practical use…It is not a question of whether the substance simply has an effect, but the ‘what’ and the ‘how’ of this effect.
In Reil’s seventh rule, he states the importance of the scientific method in the study of pharmacology. The critical importance of experiential learning and the process of inductive logic are emphasized.
7) The effects of drugs must be established either through direct experience or from conclusions, which were clearly able to be drawn from direct experience. Their characteristics have to be clearly described… Isolated observations must be collated and general results deduced according to certain rules (e.g. frequency, causality).
In Reil’s eighth and final rule, he returns to his call for improved terminology, with greater precision in the words we use to describe our experimental findings. After stating his rule, he goes on to offer a number of specific examples in support of his argument for a dedicated, technical language of pharmacology.
8) Finally, the terminology used in pharmacology deserves sharp criticism. The meaning we give to words needs to be more precise, more expansive and more accurate. Without this improvement we will remain virtually unintelligible to each other.
His rules in perspective
In the second half of the 18th century, medical practice was in turmoil after a period of relative stagnation lasting more than 500 years. Through numerous discoveries and a wholly different approach, medieval medicine was giving way to a more enlightened system. As part of this, there was a growing desire to place medical practice on a much more solid scientific foundation. The term pharmacology itself was probably coined in the late 17th century, but acquired its modern definition in 1791 from Friedrich Albrecht Karl Gren, a German chemist, physician and friend of Reil. Gren distinguished the science of the action of drugs from the mere description and collection of drugs. This cataloguing of drugs was materia medica, while pharmacology was a science. A science, however, needed a rational framework and a method, and these Reil sought to provide.
Reil’s rules may be seen as a natural development in this context. However, Reil was not the first to propose a set of rules to formalise the study and evaluation of drugs. The ancient Roman physician and philosopher Galen and the 11th century Persian polymath Avicenna, as well as medieval physicians who followed them, did the same.
An obvious question to address is: how much was Reil influenced by his predecessors?
Galen and Avicenna had dominated the medical curriculum for centuries. Galen’s works were widely read and studied in their original Greek and from the 15th century in Latin translations. They formed part of the core curriculum in most European medical schools but by the Renaissance their authority was being questioned. By the mid to late 17th century they were no longer taught at the European medical schools.
Similarly, Avicenna’s famous Canon of Medicine was available in Latin throughout the later medieval period and was probably first translated in the second half of the 12th century. The Canon continued to be used in medical schools up until the late 17th to early 18th centuries. However, by the time Reil attended medical school it would have fallen out of favour, to be replaced with more contemporary texts of the medical enlightenment.
In parallel with the upheaval in medical practices in the 18th century, there was a corresponding overhaul of medical education. Medical curricula were changing to accommodate new subjects such as chemistry, botany and physiology. While the classic texts such as those of Galen might still be read, they no longer formed part of the core syllabus.
Thus, Reil would have had access to the works of Galen and Avicenna, but it is questionable whether his medical education in the 1780s would have focussed on, or even included, these classic authors’ works. It is perhaps unsurprising then that Reil’s rules differ significantly in their emphasis from those of the ancients. Like Galen and Avicenna, Reil recognized the need for appropriate experimental design, but he goes much further than his forebears in his calls for scientific rigour and for a new vocabulary to report our findings.
Reil, like many physicians of his day was not content to specialize in one area. His contributions to several branches of medicine, including pharmacology, are significant, but partly because of his premature death and partly because of his shifting interests, we had to wait until later in the 19th century to see a truly scientifically founded pharmacology.
(c) Allan Gaw 2018
This blog is a shortened version of my paper in the European Journal of Pharmacology
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