History of Pharmacology in the Netherlands and Leiden

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1859 Rudolf Buchheim Lehrbuch der Arzneimittellehre, German
1894 Stokvis BJ The British Med Journal 794-795
1907 Pekelharing CA Ned Tijdschr Geneeskd 1907(51) 8-19, Dutch
1907 van Leersum EC Ned Tijdschr Geneesk 51 47-51, Dutch
1911 Schmiedeberg IO Naunyn-Schmiedeberg's Arch. of Pharmacology Bd 67(1) 1-54
1951 Gaarenstroom JH Ned Tijdschr Geneeskd 95(10) 762-767, Dutch
1968 de Jongh SE Acta Endocrinologica 57(1) 1-15
1982 Parascandola J TiPS 3 93-94
2002 Baños JE Reverte M Bosch F TiPS 23 (6) 294-296
2002 Reverte M Baños JE TiPS 23 (3) 112
2008 Gispen WH Nijkamp FP Eur J Pharm 585 (2-3) 219
2008 van Ree JM Breimer DD TiPS 29 (4) 167-169
2008 100 year Pharmacology in the Netherlands, especially Utrecht (Dutch)

Article below adapted from TiPS June 1990 [Vol. 11], 236-239,  Elsevier, edited for internet

The history of pharmacology in the Netherlands from 1908 till 1990

Pharmacology is an active sport in the Netherlands. Each of the country's eight universities has a department of pharmacology and there are at least six government-operated research institutes. This activity owes a debt to the long history of the discipline. Rather than cataloguing today's research or providing a rigid historical study, This article presents a pharmacologist's perspective on the sources and directions of pharmacological research in the Netherlands.

ALTHOUGH PHARMACOLOGY did not develop as a distinct discipline until the early years of this century, there were several drug investigators working in the Netherlands before that time. Among them were the internist Barend Jozeph Stokvis (1834-1902), professor in Amsterdam, who wrote a textbook of materia medica1 which is still fascinating to read, and C.A. Pekelharing (1848-1922) (J. Nutr. 1964 83: 1 1-9) in Utrecht, who was originally a physiological chemist but also worked on anatomy, histology, general pathology and pharmacology.

However, experimental pharmacology flowered with the appointments as professors of pharmacology of Rudolph Magnus (1873-1927) in 1908 in Utrecht, and Ernst Laqueur (Dutch), (German) (1880-1947) in 1920 in Amsterdam. Their heritage can be traced in Dutch pharmacology up to the present day. Both came from Germany, but they had few common scientific interests.


The influence of Rudolph Magnus

Magnus, who had worked in R. Gottlieb's laboratory in Heidelberg, was mainly interested in direct effects of drug molecules on organ functions. Hence, experiments with isolated preparations were methodologically of prime importance; the 'Magnus apparatus' for in-vitro studies of smooth muscle preparations is still in use. His successors evolved this approach to research on drug-receptor interactions, structure-activity relationships and drug design. Magnus's 'scientific grandson' E.J. Ariëns (1918-2002) English (Levensberichten KNAW) and the latter's co-workers - especially J.M. van Rossum and A.M. Simonis - made fundamental contributions to this area. It is commonly assumed that Ariëns's studies are mainly inspired by A.J. Clark's work; however, roots are evident in Magnus's laboratory: there, in 1923 a remarkable little textbook2 on pharmacology, ahead of its time, was written by W. Storm van Leeuwen (1882-1933). Storm van Leeuwen medaille. His career was unconventional for a scientist: after early retirement as a cavalry officer he studied medicine, he came to work with Magnus and in 1920 became professor of pharmacology in Leiden. His interest shifted to the immunological aspects of allergy. When the university board rejected his request for hospital beds at the university hospital, he founded his own private clinic for allergic diseases, which attracted many - mostly foreign - patients. The good citizens of Leiden respectfully watched the awkward high structures near the clinic where 'unpolluted' (by pollen) air was taken in and filtered for the 'allergen-free' patient rooms. After his early death in 1933 allergology was continued by clinical investigators.

Magnus's successor was his pupil U.G. Bijlsma (1892-1977). In addition to his own cardiovascular investigations, he maintained relations with the pharmaceutical firm of Brocades (today, after mergers, Gist-Brocades). This ultimately led to the establishment of a pharmacochemistry department there, led by W.Th. Nauta (1913-1986), who later founded a similar laboratory at the (Protestant) Free University in Amsterdam. He was succeeded by the present incumbent H. Timmerman. The 'receptorologist' J. Zaagsma in Groningen is another of Nauta's disciples although he was also strongly influenced by Ariëns.

W. Lammers (b. 1922) is another notable student of Bijlsma's; from a stay in W. Feldberg's laboratory in the UK he brought home an interest in the effects of drugs on electrophysiological phenomena. He introduced this topic in Groningen, when he was appointed chairman of the department of pharmacology in 1965. Several years earlier, when working in what is now the government Laboratory of Public Health and Environmental Protection (RIVM) in Bilthoven, he had acquired experience in drug metabolism which he also transferred to his new position. These two lines of research are being continued after his recent retirement by A. den Hertog and D.K.F. Meijer, respectively.

E. J. Ariëns (1918-2002), Bijlsma's best known student, became in the mid-1950s the first professor of pharmacology at the new faculty of medicine of the Catholic University in Nijmegen. In continuing his basic studies on drug-receptor interactions he has investigated its important implications for drug design, in recent years especially with regard to the stereochemical specificity of drugs. His abundant scientific and editorial activities have made him an influential person in the world of pharmacology. To his school belong several prominent investigators of today's generation, among them A.R. Cools, C.A.M. van Ginneken and H.A.J. Struyker Boudier.

In his earlier years, Ariëns closely cooperated with J.M. van Rossum (b. 1930). However, van Rossum's main interest gradually shifted to pharmacokinetics, which he endowed with important theoretical and experimental contributions. Of his pupils, D.D. Breimer (b. 1943) became in the mid-1980s one of the founders of the Center for Bio-pharmaceutical Sciences at the University of Leiden, an institute for coordinated multidisciplinary drug studies.

In van Rossum's career, it is interesting to observe a gradual divergence from the 'Magnus line': from studies of direct interactions between drugs and receptors his interest shifted to a 'whole-body' approach. In pharmacokinetics and particularly in studying relationships between pharmacokinetics and pharmacodynamics, various interacting systems in the organism have to be considered. Much of van Rossum's later work consists of mathematical descriptions of such complicated interactions.

A similar shift in emphasis towards regulatory systems can be found in Magnus's own research, especially in his famous studies on body posture, performed together with de Kleijn. These aspects had received little attention in his earlier work.


The influence of Ernst Laqueur (Dutch), (German)

The pharmacology of regulatory systems, a sideline in the school of Magnus, gradually became the main object of research in the school of the other 'founding father' of Dutch pharmacology, Ernst Laqueur. His career in the Netherlands started in 1912 in the famous physiology department of H. J. Hamburger (1859-1924) in Groningen. There his interest in hormones, at first especially insulin, was aroused. Experimental endocrinology in the Netherlands spread from Amsterdam after his appointment as professor there in 1920.

Laqueur's approach to science was totally different from Magnus's. If we regard Magnus as the busy participant in many of the experiments in his laboratory, Laqueur may be characterized as an inspiring organizer and manager of science, attracting, selecting and encouraging talented young scientists. A special feature of Laqueur's organizing skills emerged from his contacts with Saal van Zwanenberg (1889-1974), director of a large meat cannery in the south of the Netherlands. He provided Laqueur's laboratory with the slaughterhouse material needed for hormone extractions. Commercial prospects resulted in the founding of the pharmaceutical firm of Organon in 1923 and its funding of much of Laqueur's research. Such a cooperation between university and industry was very unusual at that time and caused raised eyebrows, but it created the intellectual climate and material conditions for scientific successes like the discovery of testosterone by David et al.3,4 in 1935.

Organon retained close bonds with academia, with industrial scientists becoming professors and vice versa. This process started with the Austrian Marius Tausk  (1902-1990). After his training in pharmacology by Otto Loewi in Graz and a brief sojourn in Laqueur's laboratory, he became scientific director of Organon, and remained so until his retirement in 1967. He was an inspiring leader, an internationally renowned authority in endocrinology and later an outstanding professor of endocrinology in Utrecht.

Perhaps the most prominent disciple of Laqueur was Samuel E. de Jongh (1898-1976). See also KNAW digitallibrary: (Levensberichten KNAW) (Dutch). In 1934 he accepted the professorship of pharmacology in Leiden as successor to W. Storm van Leeuwen. He became known by two main fields of activity: he laid down the fundamental principles of general pharmacology in a small book which became a classic in the Netherlands and Germany. The other field, his experimental work, consisted of a long series of very clever but technically astonishingly simple experiments which enlarged our knowledge of pituitary-gonadal interrelationships. Although held in high esteem in the Dutch-speaking scientific community, he was too little known abroad, partly because much of this work was done under wartime conditions but also because his modesty held him back from the rostrum of international congresses. Several of his findings were later rediscovered and claimed by others; he observed this with intellectual satisfaction but without jealousy.

His co-workers before and during the war years were J.H. Gaarenstroom - another pupil of Laqueur's - who later became professor of pharmacology in Groningen, and G.A. Overbeek, who went to Organon as principal pharmacologist. In Leiden, de Jongh's endocrinological work was continued by G.P. van Rees (b. 1928). As his successor, I pursued his more generalistic line of research. My main interest shifted from endocrinology to neuropharmacology during and after a collaboration with Dixon M. Woodbury and Louis S. Goodman in Salt Lake City. In addition, I was engaged in the organization of ethical review of human and animal experimentation.

David de Wied (1925-2004) (Dutch), See also KNAW digitallibrary: levensberichten (Dutch), began working in Gaarenstroom's laboratory in Groningen while still a medical student. His initial studies focused on pituitary-adrenal relationships. After being professor of endocrinology in Groningen (1961), he was appointed, on Bijlsma's retirement in 1962, professor of pharmacology in Utrecht. His associate P.G. Smelik joined him there, but soon moved to the chair of pharmacology at the Free University in Amsterdam. There, his work remained in the neuroendocrinological area, but later his co-workers A.H. Mulder and F.J.H. Tilders broadened their research to other areas of neuropharmacology.

Although de Wied named his laboratory after its founder Rudolph Magnus, he may be considered as fully belonging to the Laqueur tradition. Inspired by Mirsky and Miller during his stay in Pittsburgh, de Wied expanded research on ACTH and vasopressin to the central neuro- and psycho-pharmacological actions of these pituitary hormones. Experiments by his group, performed in cooperation with scientists from Organon, demonstrated the importance of neuro-peptides as substances with modulatory influence on brain functions; these ideas had a profound influence on neuropharmacological concepts. De Wied assembled a large group, which included J.M. van Ree, Tj.B. van Wimersma Greidanus and his direct successor, W.H. Gispen. The work of J. Bruinvels, who recently retired as professor of neuropsychopharmacology in Rotterdam, is thematically connected with this group.

De Wied was also very involved with the European Journal of Pharmacology; under his editorship it became one of the leading journals in the field.

Other influences

From this rapid journey through the history of pharmacology in the Netherlands, two main currents are discernible, meandering from university to university. Of course, there were connecting channels between these main 'rivers', and tributaries - originating from both home and abroad -flowing into them.

P.A. van Zwieten (Dutch), at the University of Amsterdam, is a disciple of F.Th. von Brücke in Vienna and H. Lüllmann in Kiel and works mostly on cardiovascular pharmacology. I.L. Bonta at the University of Rotterdam was a student of B. von Issekutz's in Budapest, but was also influenced by the 'Laqueur spirit' while working with Organon. His speciality is immunopharmacology. He participates as a pharmacologist in the closely knit multi-disciplinary network of immunol-ogists in the Netherlands. His colleague in Rotterdam, P. Saxena, who works on cardiovascular aspects of migraine research, was trained in K. Bhargava's laboratory in Lucknow, India. P.C. Molenaar and R.L. Polak (the latter now retired), working in Leiden on neuromuscular physiology and pharmacology are closely linked to the British neurophysiologists R. Miledi and associates.

Several major influences on Dutch pharmacology originated within the country itself. One of the founders of biological toxicology in the Netherlands is H. van Genderen (b. 1915). A biologist by training, he first worked in the government Laboratory for Public Health and Environmental Protection (RIVM) in Bilthoven where he developed a special interest in environmental toxicology. After his appointment as professor of veterinary pharmacology in Utrecht in 1961 he initiated several new lines of research, including neurotoxicology (J.M.M. van den Bercken) and temperature regulation in cattle (A.S.J.P.A.M. van Miert). At the RIVM he was succeeded by J. van Noordwijk, whose main interest in applied drug research is of importance for European drug legislation and standardization.

Another genuine Dutch branch of pharmacology is that of etho-pharmacology. Ethology, as a specialization in biology, has a long history in the Netherlands, starting before World War II with Niko Tinbergen in Leiden, (later Oxford). Ethopharmacology as a hybrid of ethology and psycho-pharmacology has developed rapidly since the 1960s, especially in the pharmacology department of the University of Leiden (A.M. van der Poel, M.R. Kruk, J. Mos), where studies were integrated with neuroanatomy and neuropharmacology. Members of this group have moved to the industrial laboratories of Duphar near Amsterdam and are engaged in the development of new psychotropic drugs.

That experimental pharmacology in the Netherlands is still of international standard will be evident from Dutch contributions to the IUPHAR International Congress of Pharmacology. The main areas of investigation are neuropharmacology, neuroendocrinology, receptor pharmacology and drug metabolism. Dutch pharmacologists working abroad are highly regarded, and many scientists come from other countries to work in the Netherlands, particularly in the pharmaceutical industry. As elsewhere, Dutch pharmacology faces the problems of increasing specialization in pharmacology training (the 'universal pharmacologist' no longer exists), and heavy budget cuts. Despite this, however, pharmacology is becoming more attractive as a career among Dutch graduates - especially pharmacists. This must be due in no small measure to the example of eminent scientists working in this discipline.

Acknowledgements
The author thanks Prof. H. Beukers for advice on the history of medicine, and Ms R.H.F. de Ru for linguistic assistance.

Erik L. Noach (1921-2008)

Office of the Pharmaceutical Medicine Course, University of Leiden, Wassenaarseweg 62, Leiden, Netherlands.

References

  1. Stokvis, B.J. (1906)  Voordrachten  over Geneesmiddelleer  (3rd  edn,  revised  by Zeehuisen, H.), De Erven F. Bohn
  2. Storm van Leeuwen, W. (1923) Grondbeginselen  der Algemeene  Pharmacologie voor Studenten in de medicijnen en voor Artsen, J.P. Wolters
  3. David, K., Dingemanse, E., Freud, J. and Laqueur, E. (1935) Hoppe-Seylers  Z Physiol Chem. 233 (5-6), 281-282
  4. David, K. (1935) Acta Brevia Neerl. 5, 85-86
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