View of Oswald Schmiedeberg – the “father” of experimental pharmacology

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

EDITORIAL

UDC: 615:378 DOI: 10.18413/2313-8971-2017-3-4-3-19

Mikhail V. Pokrovskii1

Tatyana V. Avtina T.

Elena V. Zakharova

Yulia. V. Belousova

OSWALD SCHMIEDEBERG –THE “FATHER” OF

EXPERIMENTAL PHARMACOLOGY

Belgorod State National Research University, 85 Pobedy St., Belgorod, 308015 Russia

Corresponding author, 1e-mail: pokrovskii@bsu.edu.ru

“Our tribute to the memory of the Teachers

and those who were pioneers of pharmacology

is an invaluable gift to our descendants”

Abstract

Biography. Oswald Schmiedeberg (1838-1921) was a son of a bailiff and a maid of

honour, the eldest of the six children in the family. He was born and educated in the

Russian Empire.

Scientific activity. All his life he was completely devoted to science, making

experimental pharmacology an independent scientific discipline, and was able to bring it

to the international level. O. Schmiedeberg studied the action of muscarine and nicotine,

digitoxin, hypnotics and analeptics. He was the first to introduce the concept of

―pharmacodynamics‖ and ―pharmacokinetics‖ of a drug. With his participation, the

world‘s first pharmacological journal was founded, which is still published today.

Science school. Working for many years at the University of Strasbourg, Schmiedeberg

managed to educate about 120 students – professors from 20 countries of the world,

many of whom later founded experimental pharmacology in their countries, for

example, Abel in the USA, and N.P. Kravkov in Russia. Scientific activity of

Schmiedeberg influenced scholars of his time and for generations to come, creating the

preconditions for new high-profile discoveries and even for receiving Nobel prizes. But

Oswald Schmiedeberg failed to obtain this high award himself, though he had been

nominated 14 times.

Biography

Oswald Johann Ernst Schmiedeberg

(Figure 1) was born on 29.09.1838 (on

11.10.1838 New Style) in Gut-Laizane, in

Courland (Laidze parish, Talsi municipality,

Latvia), which was at that time part of the

Russian Empire.

His father, Wilhelm Ludwig Schmiedeberg

was born in 1809 in Vindau (Latvia), a son of

Johann Ernst (a mechanic in Libau) and

Gertrude Borchet. He worked as a bailiff in

Leidzen, later took charge of the forestry in

Permisküla, and Paggar (Estonia), died in 1878

in Dorpat. The mother of O. Schmiedeberg,

Anna Lucy Bernard, was born in Lausanne

(Switzerland) in 1813, a daughter of Johann

Bernard, a watchmaker in Lausanne. She

worked as a maid of honor and died in 1871.

His brother, Johann Julius Rudolf, was born in

1840, worked as a forester in Estonia and was

Rus.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

never married. Oswald Schmiedeberg was the eldest of the six siblings [1, 2].

Fig. 1. Oswald Schmiedeberg [3]

After finishing a primary school in

Permisküla, Schmiedeberg studied at a district

school of Dorpat (today Tartu, Estonia) from

1852 to 1854. In 1855 he studied at the

gymnasium in Dorpat, which he successfully

finished in 1859, after which he entered the

Medical Faculty of the University of Dorpat,

where he was a student till 1866. The Imperial

University of Dorpat (The Imperial University

of Yuryev from 1893 to 1918) was one of the

oldest universities in the imperial Russia;

nowadays it is The University of Tartu in

Estonia (Figure 2) [4, 5, 6].

Schmiedeberg studied at the university at

one of the best periods of the Medical Faculty

of the University of Dorpat, which was

connected with the hey day of Enlightenment in

Russia in the second half of the 19th century. In

the 1860s, when in all spheres of scientific

activity there was a definite change for the

better, a system of freelance university lecturers

(privat-docents) started to develop at the

Medical Faculty, where only after 1863, young

scientists (privat-docents) began to work on a

constant basis. All this, undoubtedly, was due

to the Enlightenment process in Russia at that

period. The very development of the system of

freelance university lecturers (privat-docents)

at Dorpat Medical Faculty proves that at that

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

time it was in a flourishing condition, there

were those who could teach and those who

wanted to study [2].

Fig 2. The Imperial University of Dorpat, 1860 [7]

After graduating from the University of

Dorpat in 1866, O. Schmiedberg defended his

doctoral thesis On Quantitative Determination

of Chloroform in Blood and Its Behavior

Towards the Former (“Ueber die quantitative

Bestimmung des Chloroforms im Blute u. Sein

Verhalten gegen dasselbe”) under the

supervision of Professor Rudolf Buchheim [8,

9, 10, 11]. The title page of the dissertation of

the scientist can be seen in Fig. 3.

Rudolf Buchheim was elected by the

Council of Dorpat University to the

Department of Pharmacology on December 30,

1846, and from October 1849 to 1867, he was

an ordinary professor at that department. His

fruitful professorship and his constant desire to

recognize pharmacology as a science

independent of therapy, putting it on the

experimental research basis, made him so

famous that foreign universities such as The

University of Breslau, The University of Bonn

and The University of Giessen tried to hire him.

R. Buchheim was the first scientist who put

pharmacology on sound scientific grounds, and

the manual that he compiled included for the

first time the description of the physiological

effect of agents, on which their therapeutic

application was based. The vision of Buchheim

served as the cornerstone of modern

pharmacology. One of the important

achievements in Buchheim‘s scientific life is

considered to have been the education of his

follower in science, one of the greatest

scientists – Oswald Schmiedeberg [2, 13].

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

Fig 3. Title page of the thesis by O. Schmiedeberg [12]

While working at Dorpat University,

Schmiedeberg actively cooperated in his

research with outstanding scientists of that

time: a biochemist Karl Schmidt (1822-1894),

anatomist Friedrich Heinrich Bidder (1810-

1894), physiologist Karl Wilhelm von Kupffer

(1829-1902), etc.

Karl Ernst Heinrich Schmidt was a Russian

chemist of German-Baltic descent, a professor

at the University of Dorpat, and a

corresponding member of the Petersburg

Academy of Sciences (1873). He supervised a

degree project of Wilhelm Ostwald, a Nobel

laureate in Chemistry, when the latter was

seeking a Doctor of Philosophy degree [2, 14].

Georg Friedrich Carl Heinrich Bidder was

a Russian physiologist and anatomist of

German-Baltic descent, Professor and Rector of

the Imperial University of Dorpat (1857-1864),

acorresponding member (1857) and an

honorary member (1884) of St. Petersburg

Academy of Sciences. In 1869, F.H. Bidder

retired as Professor Emeritus [15, 16].

Carl Schmidt and Friedrich Bidder were

the first scientists who managed to dispel the

doubts of Henry Bence Jones, who had

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

published an article in The Lancet magazine in

1850, in which he wrote: ―The gastric juice is a

strongly acidic liquid secreted by the stomach

... . Which acid still remains unknown. Salt,

phosphoric, acetic, lactic and butyric acids are

said to be present in gastric juice‖ [17]. In

1852, F. Bidder and C. Schmidt published the

book Die Verdauungssaefte und der

Stoffwechsel (Digestive Juices and

Metabolism), in which they presented the

results of a quantitative analysis of gastric juice

collected from various species of live animals,

confirming the fact that the stomach normally

secretes hydrochloric acid [15].

Karl Wilhelm Kupfer, a German anatomist,

histologist and embryologist, was a student of

Friedrich Bidder, a prosector and an

extraordinary professor at the University of

Dorpat (1856–1866). His studies, conducted

jointly with Bidder, were on the structure of the

spinal cord. In honor of Kupfer, specialized

liver macrophages the main function of which

is capturing and processing old nonfunctional

blood cells were called Kupffer cells [18].

After defending his dissertation in 1866, O.

Schmiedberg became Assistant Professor to R.

Buchheim at the Pharmacological Institute, and

in 1867 he received the title of Privat-docent.

When Buchheim left Dorpat after getting an

invitation from the University of Giessen,

Schmiedeberg was asked to give lectures on

pharmacology and dietics. In 1868, he was

appointed Full-time Associate Professor, and in

1869 - an Extraordinary Professor of

Pharmacology, Dietics and History of

Medicine. After being appointed an

Extraordinary Professor, Schmiedeber was

appointed Director of the Pharmacological

Institute, which he had held since the departure

of Buchheim.

Together with the renowned scientists of

the University of Dorpat, Schmiedeberg made a

number of discoveries. Before 1870, his studies

on physiological chemistry had led to the

discovery of sulfuric acid in the urine of cats

and dogs. Together with Ernest Bergman, he

conducted research on the poison of rotting

substances and discovered sepsin in form of its

sulfuric acid salt. Together with Dr. Richard

Koppe, Schmiedeberg in 1868 studied the

composition of the fly agaric (Agaricus

muscarius), which led to the isolation of

muscarin, the properties of which were studied

in detail by both authors. Over that time, ten

scientific dissertations were completed under

the supervision by O. Schmiedeberg [2, 5].

In 1870, Schmiedeberg continued his

education in Germany, in Leipzig. He spent a

whole year at Leipzig University, working

together with the outstanding physiologist Karl

Friedrich Wilhelm Ludwig (1816-1895). O.

Schmiedberg successfully used the kymograph

(device for recording blood pressure) invented

by K. Ludwig in his scientific experiments and

reasonably considered K. Ludwig one of his

scientific teachers [19]. Fig. 4 shows a

kymogram obtained on smoked paper.

Fig. 4. Example of kymogram on smoked paper [20]

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

In 1871, Oswald Schmiedeberg became

Full Professor of Pharmacology, Dietics and

History of Medicine at the University of

Dorpat. From 1871 to 1872, Schmiedeberg

visited Bern and Kцnigsberg (Prussia), and in

1872, Schmiedeberg resigned from the

University of Dorpat after accepting a position

at the just-founded University of Strasbourg,

where later he was to get engaged in research

and teaching for the next 46 years, started his

own scientific school and was the Director of

the Pharmacological Institute [2].

After arriving at the University of

Strasbourg, his scientific laboratory was a very

small room in a hospital at Place de l'Hфpital.

Along with promoting research in experimental

pharmacology, in 1887 the University

administration assigned a new spacious

building for the laboratory, the building having

been designed by Schmiedeberg himself, in

cooperation with the architect Otto Warth

(1845-1918). Schmiedeberg‘s office and

personal laboratory were on the second floor,

the laboratory at the corner with the balcony,

the office immediately to the left with the bow

window (Figure 5) [21, 22].

The University of Strasbourg was one of

the most prestigious and best schools at the

time. Along with Schmiedeberg, there worked

a number of prominent scientists. Among them

was anatomist Heinrich Wilhelm Waldeyer

(1836-1921), who was engaged in anatomical,

histological, comparative-anatomical and

embryological studies. In 1884, he published a

paper in which he gave a detailed description of

the embryogenesis, structure and functional

significance of the pharyngeal lymphoid tissue

(Pirogov-Waldeyer’s ring). In 1888, for the

first time he used the term ―chromosome‖, was

one of the first supporters of Cajal‘s neural

theory and suggested the term ―neuron‖ [23].

Other famous scholars were Felix Hoppe-

Seyler (1825-1895), one of the founders of the

Department of Biochemistry and the founder of

the journal of physiological chemistry and

pathologist Friedrich Daniel von

Recklinghausen (1833-1910), whose research

papers were on neurofibromatosis, parathyroid

osteodystrophy and fibrous ostitis (these

diseases, as well as a number of other

pathological processes were later called by his

name), and who studied rickets and

osteomalacies, which later became classical.

Schmiedeberg was the youngest among

colleague scientists.

Fig. 5 The Institute of Pharmacology in Strassburg,1877 [21]

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.

December. 2017. 3(4). Research Result: Pharmacology and Clinical Pharmacology rrpharmacology.ru

In the period from 1918 to 1919, O.

Schmiedeberg moved to Baden-Baden, where

he lived till his death. His friend in Baden-

Baden was B. Naunyn. They were neighbors

and often would take a walk along a forest road

in Baden-Baden, which is now called Schriever

Lane [24].

His view of pharmacology as an

independent exact science, O. Schmiedeberg

laid in the third edition of his work

Fundamentals of Pharmacology, for which he

tried to provide a rational basis in contrast to

purely subjective empiricism [15].

Schmiedeberg‘s Alma mater, The

University of Dorpat, after the fall of the

Russian Empire in 1918 was intervened by the

Germans. Due to an increase of Russophobia

and the First World War, the University faculty

members were evacuated to Voronezh, where

they made up the basis for Voronezh State

University [21, 22, 25].

Oswald Schmiedeberg died on

12.07.1921, at the age of 83.

Scientific activity

The vast knowledge acquired when

cooperating with many professors in the field

of medicine and chemistry allowed O.

Schmiedeberg to make a number of

discoveries.

Muscarine, nicotine. In 1869, in the

monograph by Oswald Schmiedeberg and

paramedic Robert Koppe, there appeared for

the first time an article about muscarin as a

toxic alkaloid extracted from fly-agarics

(Agaricus muscarius L.) [26]. When working

together, the scientists isolated pure poison

from fly-agarics picked in the vicinity of

Dorpat and described its pharmacological

effects, named them muscarinic and proved that

the poison possessed an antagonistic action

towards atropine. Antagonism manifested by

atropine against muscarinic receptors was a

prototype of competitive antagonism. The work

in question was of fundamental importance for

pharmacology and medicine as a whole and

resulted in the discovery of the chemical

transfer of impulse in synapses by Otto Loewi

(1873-1961). As O.Shmideberg and R. Koppe

wrote: ―These effects not only are of high

scientific, but also practical interest, since their

study has led to the discovery of a

physiological antidote to the poison of fly-

agaric, which will help avoid the life-

threatening consequences of accidental

poisoning with this widespread species of

mushrooms. Thus, poisoning can probably be

completely avoided.

Soon after studying the pharmacological

affects of muscarine, O. Schmiedeberg began

to study another pharmacological agent –

nicotine. The Professor was the first in Dorpat

who got interested in this issue, and he further

continued his studies in Karl Ludwig‘s

laboratory in Leipzig. Schmiedeberg proved

that nicotine suppressed the inhibitory effect of

the vagus nerve on the heart and conlcluded

that this happened due to ganglionic blockade.

That theory was examined thoroughly and was

later confirmed in the teachings by John

Newport Langley (1852-1925) when studying

the autonomic nervous system [27, 28].

About 150 years have passed since the

discovery of the pharmacological effects of

muscarin and nicotine, but modern textbooks

on pharmacology still describe vegetotrophic

agents basing on Schmiedeberg‘s

understanding of M- and N-cholinergic

receptors, their agonists and antagonists.

Digitalis. One of the most famous

works by O. Schmiedeberg and the main

direction of his research is rightly considered to

have been the study of digitalis, namely

alkaloids isolated from this flower. Despite the

fact that there was little information about the

medicinal properties of digitalis at that time,

this topic caused a lot of arguments and

controversy. It was O. Schmiedeberg who

managed to work out many questions.

In 1874, when Schmiedeberg returned

from France, he for the first time isolated a

separate substance from the collected red

flowers of the digitalis and called it digitoxin.

This substance was proved to have a serious

effect on the activity of the cardiovascular

system. His colleague, Robert Koppe, agreed to

conduct an experiment to study the

pharmacological effects of digitalis on his own

body. During the experiment, R. Koppe

recorded the pulse on his wrist (Figure 6).

Ingestion of 3.5 mg of digitoxin led to serious

poisoning, as well as to the side effects in form

of arrhythmia (Pulsus bigeminus).

Pokrovskii M.V., Avtina T.V., Zakharova E.V., Belousova Yulia V. Oswald Schmiedeberg – the

“father” of experimental pharmacology. Research Result: Pharmacology and Clinical

Pharmacology. 2017;3(4):3-19.