Mani: The historical background of Clinical Chemistry
311
J. Clin. Chem. Clin. Biochem.
Vol. 19,1981, pp. 311-322
The Historical Background of Clinical Chemistry1)
By N. Mani
Medizinhistorisches Institut der Universität Bonn
(Received November 30,1979)
Summary: The discipline of chemical pathology, earlier known as pathological chemistry, arose from the attempt to
apply chemistry to medicine. Two main origins of the subject can be identified: the development of scientific research
in medicine, and the emergence of organic chemistry and physiological chemistry.
The development of clinical chemistry and its two historical roots in the 19th century are traced from their beginnings, together with the contributions from biology and natural philosophy.
A vitalistic view of chemistry in the biosciences, the identification of natural products and the study of their metabolism all favoured the early establishment of clinical chemistry at the end of the first half of the 19th century. This
was followed by a rise of fundamental research in physiological chemistry, while clinical laboratories remained as
application-orientated adjuncts of clinical medicine, with the task of diagnosis.
Die geschichtlichen Grundlagen der Klinischen Chemie
Zusammenfassung: Die aus den Bemühungen und Versuchen, die Chemie auf die Medizin anzuwenden hervorgegangene Pathologische Chemie hat zwei Hauptwurzeln: die Entwickling einer wissenschaftlichen Forschung in der Medizin sowie die Entfaltung der Organischen .Chemie und der Physiologischen Chemie.
Die Geschichte der Klinischen Chemie und ihrer beiden Wurzeln im 19. Jahrhundert wird von dessen Beginn an unter
Berücksichtigung der Beiträge von Biologie und Naturphilosophie dargestellt. Vitalistische Betrachtung der Chemie in
den Biowissenschaften, Identifizierung von Naturstoffen und Untersuchung ihres Stoffwechsels begünstigten eine
frühe Blüte der Klinischen Chemie Ende der l. Hälfte des 19. Jahrhunderts. Darauffolgende Hinwendung zur Grundlagenforschung in der Physiologischen Chemie ließ die klinischen Laboratorien vorerst anwendungsorientierte Anhängsel der klinischen Medizin mit Aufgaben in der Diagnostik bleiben.
Introduction
Scientific Orientation of Medicine
In the first half of the nineteenth century physicians, pathologists and chemists made early attempts to apply
chemistry to medicine in the areas of medical diagnosis,
description of morbid processes and therapeutic control.
This new branch, associating medicine and chemistry,
was generally called pathological chemistry.
In the first half of the nineteenth century the sciences
developed vigorously. The atomic composition of inorganic and organic matter was postulated. Organic analysis revealed the elementary composition of organized bodies. The law of conservation of energy enounced by
Julius Robert Mayer and Hermann Helmholtz was applied to dead and living matter; the divine flame of vital
heat was reduced to a problem of energetic balance.
Pathological chemistry has two main roots:
I) A scientific, empirical and experimental orientation
of medical research
II) The emergence of organic and physiological chemistry
^Lecture given at the Symposium on History of Clinical Chemistry, III. European Congress of Clinical Chemistry, Brighton,
June 3-8,1979
0340-076X/81/0019-0311 $02.00
© by Walter de Gruyter & Co. · Berlin · New York
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Biology
In biology, morphological research opened new fields.
In 1812 Georges Cuvier published a monumental work
founding the discipline of paleontology: Researches on
the fossil bones of quadrupeds (1). In this work Cuvier
clearly distinguished between extinct and recent species,
and in his Comparative Anatomy (2) he enounced the
principle of correlation of organs which permitted the reconstruction of a complete animal organism from preserved fragments. Balzac in his "Peau de Chagrin" praised Cuvier as a true poet, recreating from pale bony fragments a whole living world of a remonte past. In his Philosophie Zoologique (3) J. B. Lamarck boldly asserted
that recent species were the descendants of extinct species. The enormous plastic potency of living organisms
allowed adaptive variations to environmental needs.
These variations were hereditary and led to the formation of new species. K. E. von Baer discovered the mammalian ovum (4), described the germlayers of the embryo, differentiated basic types of the animal kingdom
(e. g. the vertebrate type) and characterized embryonic
development as a gradual differentiation of the germ towards individualization and independence within the
boundaries of its type (5).
Mani: The historical background of Clinical Chemistry
mic idea of circular motion was present in the circulation
of the blood, the common idea of a vertebral type was
materialized in the many species and groups of the vertebrate animals. The inner vision of ideas was considered
to be the ultimate goal of science; the empirical and experimental analysis which endeavored to establish causal
relations did not seem to give decisive answers to the inquiring mind.
Scientific physiology and medicine
Between 1820 and 1850 opposition to extreme vitalism
and speculative Philosophy of Nature gradually arose.
F. Magendie (11) physician and physiologist, who occupied the prestigious chair of medicine at the'College de
France, developed the program of a radically renewed
physiology founded on empirical research and experimental data and deriving its knowledge exclusively from
positive facts. The vital phenomena, he stressed, have to
be studied with the experimental method. Around 1830
he expressed his conviction that in the near future the
life sciences would be intimately connected with the physical sciences, adopting the same severity of method, definite language and certainty of results (12). He demonstrated the venous resorption of poisons (13), he inaugu/. E. Purkyne (6) and Th. Schwann (7) described and re- rated feeding experiments with isolated nutrients in order to ascertain their individual nutritional value (14).
cognized the cellular composition of the animal body;
the microscopical investigation of disease led to the foun- Medicine, he proclaimed, is physiology of the sick man
(15). In Germany the physiologist and biologist Johandation of Cellular Pathology by R. Virchow, in which
disease was considered as a material morbid process at the nes Müller (16) freed the biological sciences from the specellular level (8) .
culative spell of the Philosophy of Nature and led a whole
generation of physicians and biologists back to empirical
research. In his inaugural lecture delivered in 1824 at
Vitalistic doctrines (9)
Bonn /. Müller stated: "Abstract thinking on Nature is
As a reaction to the mechanistic rationalism of the Age
not the field of the physiologist; the physiologist expeof Enlightenment, physicians and natural philosophers of riences nature in order to think it" (17).
the late eighteenth and early nineteenth century emphaOn the other handM///er, althougjh very dedicated to desized again a specific autonomy of vital phenomena.
tailed experimental and painstaking morphological reThese could not be reduced exclusively to mechanical
search, still believed in a "creative organic force" (18)
processes obeying the laws of inorganic dead matter. The
and in specific vital properties of organic structures as reconcept of vital force reaches from the assumption of an
vealed in his law of "Specific Sensory Energy" (19).
immaterial vital agent to the explanation of vital phenoMutter's studies covered a wide area of research: Embryomena resulting from the organization of living tissues.
logy, comparative an atomy, histology, pathological
The vital force, many assumed, regulates, harmonizes and
microscopy, sensory physiology in its relation to psychoconserves the living organism; it acts as the healing power
logy; to a lesser extent he also dealt with chemical pheof nature to overcome disease; it resists decay and susnomena of living matter. He advised e.g. the study of urea
pends the ordinary physical laws. Once the action of the
formation in starving animals in order to decide whether
vital force ceases, desorganization and putrefaction of
the source of urea was metabolized food, or whether
organic matter occurs.
urea was a decayproduct of organized living tissues (20).
Philosophy of Nature (10)
On German soil a specific and essentially speculative Philosophy of Nature exerted a strong influence on biology
and medicine in the first decades of the nineteenth century. Philosophy of Nature endeavored to gra$p the absolute idea which was the common source of spirit and
matter, of gravity and light, of body and mind. The cos-
By the 1840's eminent disciples of Mutter and other physiologists and physicians in Germany radically abandoned
the Philosophy of Nature and vitalistic doctrines. They
proclaimed that vital phenomena in health and disease
should be explained and reduced to physico-chemical
processes down to the molecular and atomic level, fh.
Schwann in his classic book on the cellular composition
of the animal body (21) viewed cell formation as a purely
J. Clin. Chem. Clin. Biochem. / Vol. 19,1981 / No. 6
Mani: The historical background of Clinical Chemistry
physical process of crystallization. He believed that the
general physical laws established by God were the unique
source of the phenomena of living and dead matter. C
Ludwig in his thesis of 1842 "De viribus physicis secretionem urinae adiuvantibus" interpreted secretion of
urine as a mechanical filtration of the urinary substances
at the glomerular level and as "endosmotic" reabsorption of water from the tubuli into the thickened blood
of the capillaries lining the tubuli (2la). E. DuBois-Reymond, the founder of modern electrophysiology, mocked
at the mysterious vital force which should resist the voracity of oxygen and should be capable of vitalizing a
dead iron atom to living blood-iron (22).
Paris Hospital Medicine (23)
Between 1800 and 1850 Paris became the most important center of clinical medicine and medical research. The
Paris school relied on precise clinical description by
means of physical diagnosis and correlated the clinical
picture to the morphological features of post mortem
examination. The extensive clinical and anatomical material was also submitted to numerical and statistical
analysis. The classical pathological atlases of/. Cruveilhier and P. F. 0. Ray er revealed a wide panorama of
macroscopic morbidity (24). Consumption or phthisis
was characterized as a nodular disease (tuberculosis)
named after its basic anatomical lesion, the tubercle (24a).
Typhoid fever whose clinical signs pointed to a nervous
disease was characterized by its primitive anatomical lesion, the inflammation of Payer's plaques with regional
lymphadenitis (25). Diseases were classified according
to their anatomical lesions, that is alterations of organic
structures and specific tissues with subsequent functional
disturbances. Diagnosis too aimed at precision; it had to
assess physical signs by means of physical diagnosis accurately and objectively. Physical diagnosis of chest diseases
by means of percussion and auscultation was, so to say,
anatomical diagnosis intra vitam, inspecting the depths
of the thoracic cavity as the name of the stethoscope indicates (26). In England too the clinico-pathqlogical
orientation was pursued. The triad ofßrighfs disease:
Dropsy, albuminous urine and granidar degeneration pf
the kidneys combined clinical, chemical and anatomical
diagnosis (27).
Physiological Medicine
Magendie1* basic program of "medicine as the physiology of the sick man" was eagerly taken up by scientificminded German physicians and physiologists. The anatomist and medical theoretician /. Henle stated in his
Textbook of Rational Pathology (28):
"The physiology of the sick and healtiiy organism are
not different; physiology and pathology are the one and
same thing".
J. Clin. Chero. Clin. Biochem. / Vol. 19, 1981 / No. 6
313
Furthermore, Henle outlined: Diseases are spontaneous
physiological experiments, and physiological experiments
are artificial diseases. The roots of modern physiology
and pathology are twofold: The rejection of the essentially speculative Philosophy of Nature and the progress
of physics and organic chemistry applied to life phenomena in health and disease (29).
In 1849 A. Virchow (30) postulated the necessity of a
pathological physiology, that is pathology integrated into physiology. Disease, he stated, is nothing but life under changed conditions, and healing means the restitution of the usual and normal conditions and processes of
life.
In 1855 W. Roser (31) supported a program of Pathology as a science (Pathologie als Naturwissenschaft). Pathology, he pointed out, is emancipated from practical medicine to an independent scientific discipline which
forms a branch of the physical sciences. Scientific pathology studies the morbid phenomena with the methods
and tools of science.
In 1859 C A. Wunderlich stated (32) "Contemporary
medicine considers its goal and duty as part of the immense and sublime Science of Nature". The important
and programmatic Journal of Rational Medicine edited
by Henle andPfeufer (since 1844) and Roser9s and Wunderlich9* Archive for Physiological Medicine (since 1842)
as well as Virchow's early articles (33) express the various endeavors of "scientific" medicine.
Organic Chemistry
In the last quarter of the eighteenth century chemical
thought and investigation entered the area of vegetable
and animal physiology. C. W. Scheele (1742-1786) identified and characterized numerous organic acids, e. g. lactic acid in sour milk and uric acid in urinary calculi and
the urine (34). /. Ingen-Housz (35) described in 1779 the
purification of irrespirable air by the green parts of
plants. The Swedish chemist T. Bergman (1735-1784)
divided the bodies into two classes, the organic and the
inorganic one (36). The very founder of organic chemistry was A. L. Lavoisier (37). He introduced combustion
analysis of organic substances and recognized the elementary composition of organic bodies. Organic matter,
he stated, is essentially composed of carbon, nitrogen,
oxygen and hydrogen. Despite the small number of elements there are numerous organic substances. These are
composed of ä basis or radical consisting of two, three
or four elements (C, H; C, H, N; or C, H, N, P); the radicals combine with oxygen to form oxides and acids.
Lavoisier emphasized that nitrogen constitutes essentially animal matter (38). The French chemist and educational reformer A F. Fourcroy stated in 1800: "I feel it
strongly and I am convinced that the efforts of chemistry will change the face of medicine" (39). Chemistry,
he said, explains the effects of digestion and respiration;
together with anatomy, chemistry will establish a sound
314
Mani: The historical background of Clinical Chemistry
substances originate? A first answer to this riddle seemed
to be given by the theory of "radicals", that is groups of
atoms reacting chemically like single atoms (e. g. benzoyl-radical). In 1837 Liebig and Dumas in a paper signed
in common and published in the Comptes Rendus
/. / Berzelius (1779-1848), trained as a physician, beof
the
Paris Academy of Sciences proclaimed a simple
came one of the leading chemists between 1810 and 1840
concept
of organic compounds (49):
(41). The first volume of his Animal Chemistry published
"In mineral chemistry the radicals are simple; in organic
in 1806 constituted the first textbook of physiological
chemistry. Already as a medical student Berzelius had re- chemistry the radicals are compound; that is all the difference. The laws of combination and of reaction are
gretted that Holler's monumental Elements of Physiology suffered from the lack of a chemical foundation unotherwise the same in these two branches of chemistry".
vailable at/fo/fer's time. Berzelius believed that in the
The dualistic theory of radicals was soon replaced by the
nineteenth century physiology would greatly benefit
theory of types and was then followed by structural chefrom chemistry (42). This induced him to deal with the
mistry (50). In 1859 A Kekule defined "organic chemischemical composition of animal substances. The early re- try as chemistry of carbon compounds". Kekule stated
sults were disappointing, however, and Berzelius turned
(51): There is "no difference between inorganic and
to problems of general chemistry, of atomic weight and
organic compounds".
of electrochemistry. Later on he took up again researches
Organic chemistry"too belongs to "pure chemistry". It
in the organic field. He published his influential Textis not identical with "physiological chemistry" which
book of Chemistry, containing substantial sections of
vegetable and animal chemistry, and wrote his important deals with the "transformations taking place within the
Annual Reports on the Progress of the Physical Sciences living organisms". Here a clear distinction between phy(43). In these reports he related the results and problems siological and organic chemistry was drawn.
of contemporary chemistry with the unchallenged authoChemical Vitalism
rity of a scientist not only acquainted with chemical research of his time but also mastering the whole field of
The views on animal chemistry were intimately connecchemistry. Leopold Gmelin, in his Textbook of Theoreti- ted with vitalistic concepts. Fourcroy believed that "anical Chemistry characterized organic chemistry with the
malization" of vegetable food was due to an innate force
following words (44):
of the animal organism (52). L. Gmelin defined "Physiological Chemistry" as chemistry under the rule of the vi"Organic Chemistry considers
tal force (53). F. Magendie believed that inorganic bodies
could be decomposed and recomposed, while organic
1) The simple organic compounds present in the vegesubstances could only be decomposed by the chemist,
table and animal body
Magendie surmised however that organic synthesis might
2) The composition of plants and animals consisting of
be possible in the future (54). In a lecture on the Progress
these simple compounds and inorganic substances: Cheand the Present State of Animal Chemistry delivered in
mical Botany and Zoology
1810 Berzelius pointed out that vital chemistry presen3) The chemical transformations of organic substances
ted an almost inscrutable riddle; and this was true at all
within the organism under the rule of the vital force: Che- levels, from glandular secretion up to psychic phenome^·
mical Physiology"
na(55):
The physician and physiological chemist C G. Lehmann
"If knowledge of the transformation of the blood to
differentiated animal chemistry in two parts,
other fluids, which in itself is analogous to ordinary chemical phenomena, is so obscure to us, how much more
1) Zoochemistry, that is the chemistry of organic comso is the renewal of the solid living parts of the body...
pounds of the animal body
Even more astonishing is the function of the brain;
2) Physiological Chemistry, which examines the chemical thought reels at the notion that, even in its most soaring
processes of the living organism.
flights or when it penetrates most deeply into the secrets
Zoochemistry is related to physiological chemistry as
of nature, it depends on a chemical process which preanatomy to physiology (45). The elementary analysis of cedes it, and the slightest error in which would destroy
organic bodies (46), the determination of relative atomic its coherence, turn it to madness or completely destroy
i t . . . and yet this is an indisputable fact."
weights (47) and the validity of the law of constant elementary composition for organic compounds (48) made Berzelius did not believe that man would "one day come
it possible to establish empirical formulae of organic sub- to understand itself and its inner nature" (56).
stances. In the first half of the nineteenth century the
In February 1828 Fr. Wähler wrote to Berzelius (57):
great question of organic chemistry recognized already
"I cannot withhold my chemical water and must tell you
by Lavoisier was: How is it possible that from relatively
few elements a large number of the most diverse organic that I can make urea without needing a kidney . . . the
foundation of physiology; chemistry alone can determine the alterations of the bodily humors and solids and
will thus assist in founding a firm basis for pathology
(40).
J. Clin. Chem. Clin. Biochem. / Vol. 19,1981 / No. 6
Mani: The historical background of Clinical Chemistry
315
ammonium salt of cyanic acid is urea (Cyansaures Ammoniak ist Harnstoff)".
bodies; they act in the inorganic and organic realm, but
particularly in the latter (68).
Wähler pointed out that ammonia and cyanic acid combined to a crystallized body in which neither ammonia
nor cyanic acid were detectable and which presented all
the chemical properties of urea. However Wähler statet
with coution: A disciple of Philosophy of Nature could
still object that cyanic acid and ammonia used in this
synthesis were obtained from organic matter (58). Berzelius answered with ironical approval. He mentioned
the "immortality" of Wähler emerging from the urine.
However turning to a serious evaluation of the "artificial
production of urea" he considered it to be an important
and beautiful discovery (59), and in his nineth Annual
Report he considered Wähler'* finding as a fine example
of isomerism (60).
In 1833 A. Pay en and/. Persoz had treated malt extract
with alcohol and had obtained a white amorphous substance which was water soluble and changed starch into
sugar. They named it diastase (69). Diastase was considered by Berzelius to be a perfect example of organic catalysis transforming the starch of germinating seed into
sugar (70). Another example of organic catalysis was
given by an albuminous substance present in almonds
which split amygdalin into the oil of bitter almonds and
hydrocyanic acid. Wähler and Liebig called it emulsin
(71).
In his 15. Annual Report on the Progress of the Physical
Sciences (1836), Berzelius stated: "We can now assume
on very good grounds that in living plants and animals
thousands of catalytic processes take place between tissues and fluids, thus giving rise to multitudes of chemical compounds" (72).
In his Textbook of Chemistry Berzelius stated in 1847:
"In living nature (chemical) elements appear to obey
other laws than in the inorganic realm; the products of
their mutual interaction are different from what we observe in inorganic nature" (61).
The discovery of the causes of this difference would be
the key opening the door to the theory of organic chemistry (62).
In his Textbook of Chemistry Berzelius surmised that
faulty vital phenomena named diseases might be due to
a weakening or alteration of catalytic forces and processes (73).
The famous chemist Liebig too believed in a vital force
with a power of chemical synthesis; this force should
Berzelius also confirmed his belief in biogenesis, that is:
build up muscular tissue from vegetable proteins (74)
life comes from life (omne vivum ex ovo) (63).
and generate the complex compounds of the brain (75).
He believed that a power incomprehensible to man and
Liebig was not an extreme vitalist, however. After Wähler
alien to dead nature had once been infused into inorgaand Liebig had prepared a series of derivatives from uric
nic matter. And this power brougjht about the conditions acid (76) some of which were identical with natural orof generation and growth of the organic world. Vital phe- ganic substances (e. g. allantoin) they concluded: "The
nomena, Berzelius was convinced, are not due to acciphilosophy of chemistry will draw from this work the
dent; they manifest the highest wisdom and appropriate
conclusion that the production of all organic materials
design. How all that occurs might remain unknown forin the laboratory, in so far as they no longer belong to
ever (64). On the other hand Berzelius was opposed to
the organism, must be regarded not only as possible, but
radical vitalism whose doctrine assumed a vital force
also as certain. Sugar, sail ein, and morphine will be articounteracting or suspending the universal physical laws.
ficially produced" (77).
Quite on the contrary, the chemists, operating within the Physiology, Liebig stated, must rely on chemistry. The
boundaries of ordinary chemical forces, have succeeded
processes of digestion, blood-formation, nutrition, sein a few instances in producing substances which othercretion and respiration are to a large extent of a chemiwise result from the vital process (65).
cal nature (78).
Berzelius outlined (66):
"In living nature we find physical and chemical phenomena so different from those of inorganic nature that the
identification of Physiological and Pathological
existence of a chemical vital force could be assumed;
Substances
however if we examine with care the circumstances, we
recognize easily the effects of the ordinary physical forIn the first decades of the nineteenth century numerous
ces put under the influence of a multitude of various
substances of physiological and pathological significance
conditions, some of which rarely occur and most of
were discovered.
which are never present in inorganic nature".
L. J. Gay-Lussac and L. J. Thenard analysed the elementary composition of starch and sugar; these substances
A first clue in explaining vital chemistry was given by
contained the elements C, H and 0, whereby hydrogen
the concept of "Catalytic Force" a term coined by Berand
oxygen were present in the ratio of water (79). The
zelius (67). A catalytic substance, Berzelius defined is
able to induce chemical change without being altered it- term "carbohydrate" was coined in 1844 by C Schmidt
(80).
self. Catalytic substances can be simple or compound
J. Gin. Chem. Clin. Biochem, / Vol. 19, 1981 / No. 6
316
Mani: The historical background of Clinical Chemistry
Bile acids
In the second decade of the nineteenth century M E.
Chevreul decomposed fats and oils into glycerine and
In 1826 L Gmelin prepared from bovine bile an organic
fatty acids; he recognized that the latter determined the
acid which contained nitrogen and formed needle-shaped
physical and chemical properties of the fatty bodies (81). crystals. He called it "cholic acid" (Cholsaure) and it
In 1827 the physician and chemist W. Prout differencorresponds to glycocholic acid (97). In 1844 M Fettentiated three classes of "alimentary matters" namely
kofer, while performing experiments to decide wether
"the saccharine, the oily and the albuminous" (82). The
bile changed sugar into fat, described the color test with
Dutch chemist G. J. Mulder coined on the advice of
sulphuric acid and sugar named after him (98).
Berzelius in 1838 the term of protein (from proteuo =
I am the first) for a core substance common to vegeBile pigments
table and animal albumins (83).
L. Gmelin differentiated two bile pigments which he
called "gall-brown" and "gall-green". The latter was
also obtained through oxidation of the brown pigment
Blood
(99). Gmelin also described the color change of bile
In the blood (84) the following substances were detreated with nitric acid, and he recommended the
scribed: Fibrin; albumin; the iron-containing coloring
application of this test for the detection of bile pigprinciple of the blood (called hematin or hematosine)
ments in urine and blood (100). In 1&Q6 Berzelius
which combined to a proteinic substance of the red
found in muscle tissues an organic acid whose chemical
globules (globulin) to form the "hematoglobulin" (85);
properties and particularly its salts were identical with
fatty bodies, cholesterin, various ill-defined "extractive
those of Scheele's lactic acid (101). In 1832 Chevreul
substances". In animals fed with starch and sugar and in
found in muscle extract a nitrogen-containing and
diabetic patients a fermentable sugar was found in the
crystaline substance which he named "cre'atme" (From
blood (86). In Bright* s disease urea was present in the
kreas, kreatos = flesh) (102). In 1847 Liebig published
blood.
his important and comprehensive investigation of meat
extracts in which he described a new substance which
could be prepared from creatine and which he named
Urine
creatinine (103). W. Prout identified in 1824 free
Urea discovered in 1773 by H. M. Rouelle (87) was
hydrochloric acid in gastric juice (104). In 1836
identified by the formation of characteristic crystals
Th. Schwann discovered in gastric juice a "digestive
after addition of nitric acid (88). Uric acid discovered
principle" (Verdauungsprincip) which he called pepsin
by C. IV. Scheele in 776 in urinary calculi was identi(105). He found that "an extremely small quantity"
fied by the murexide test (89). Cystine was discovered
of pepsin "was able to dissolve a large quantity of albuin 1810 by W. Wollaston in a bladder stone. It was
minous substance" (106).
recognized as a pathological substance and was identified by its elementary composition and the formation
Metabolic Transformations
of characteristic hexagonal plates (90). Diabetic sugar
Physicians, physiologists, chemists and agricultural
was identified by M E. Chevreul as glucose in 1815
chemists dealt with the question of how organic sub(91). It was detected by means of alcoholic fermentastances were transformed in tiie digestive and metabolic
tion, reduction of copper salts (Trommer, Fehling) and
processes.
In this field of research the methods of exby polarimetric identification (92).
perimental
physiology were combined successfully with
In 1829 Liebig found in the urine of horses and other
chemical analysis. In 1816 Magendie asked (107) the
quadruped herbivores a nitrogen-containing acid from
following question: What is the source of the organic
which benzoic acid was obtained. He named it hippuric
nitrogen, air or food?To solve the problem he fed dogs
acid after the first source from which it was obtained
with sugar, oil or butter exclusively, that is with pure
(93).
alimentary substances containing no nitrogen. The
animals survived for 32 to 36 days; some of them
developed ulcers of the cornea. The Genevan physician
Bile, Cholesterol
/. L. Prevost and the French apprentice in pharmacy
and later famous chemist/. B. Dumas investigated the
Cholesterol was discovered by B. G. F. Conradi in gallmode
of renal secretion (107a). In 1821 they removed
stones. It proved to be a substance soluble in alcohol
and crystallizing in thin plates (94). In 1815 Chevreul
the kidneys .of cats and dogs. The experimental animals
recognized that this substance of fatty appearance could fell into coma and died after a few days. In the blood of
these animals urea was detected by means of crystallizanot be saponified and he named it "Cholesterin" from
tion with nitric acid and through elementary analysis. The
Chole = bile and stereos = solid) (95). In 1824 Chevreul
conclusion was: The kidneys eliminate urea, thßy do not
and Gmelin identified cholesterol in human and bovine
produce it. After extirpation of the kidneys urea accumu^
bile (96).
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Mani: The historical background of Clinical Chemistry
317
lates in the blood. These results formed the basis of a
physiopathological explanation of Brighfs disease. The
granular kidney fails to function and urea is accumulated
in the blood (107b). As early as 1825 Charles Chossat
(1 08) stated in Magendie's Journal: The nitrogen of the
food is excreted into the urine in the form of urea. The
amount of urea is a measure of metabolized albumin.
The weight of urea multiplied by 2.7 represents the
amount of albuminous matter transformed in the metabolic process. In their classical work on digestion F. Tiedemann and L. Gmelin demonstrated the following
facts:
muscular force. He stated (118): "The chemical force
contained in the ingested food and in the inhaled oxygen is the source of two manifestations of force: motion
and heat, and the; sum of the physical forces produced
by an animal is equal to the amount of the simultaneous
chemical processes".
1) In animals fed with starch, the starch is transformed
into sugar by the digestive juices
2) Sugar is also present in the blood and urine of diabetic
patients.
2) A fermentable sugar is found in the gut and in the
blood, and to a lesser extent in the chyle and urine.
What is now the origin of this sugar? The saccharine
substances of the food? or might it be possible that the
animal organism posses a certain synthetic power similar
to plants which enables it to elaborate sugar from non
saccharaine food? To decide this question,Bernard fed
dogs exclusively with meat. Under this condition too
the blood contained a fermentable sugar. The next
question was: Where is this sugar produced? Searching
for sugar in the abdominal viscera Bernard detected
glucose in the liver parenchyma in 1848. He concluded:
The liver produces sugar; glucose is a physiological constituent of the blood; the animal organism is capable
of a chemical synthesis transforming proteins into sugar
(120).
Control animals fed exclusively with meat showed much
less sugar (109). Tiedemann and Gmelin also investigated
the digestion of fatty bodies. They found: In dogs whose
common bile duct was ligatured no bile reached the
duodenum. In these animals much less fatty bodies appeared in the intestinal lymphatic vessels (110). They
concluded: It might be that bile brings about a delicate
aqueous suspension of fatty substances which can be
resorbed(lll).
The science of nutrition profited substantially from
chemistry. /. Liebig stressed the necessity to transcend
the static "mortar chemistry" in order to investigate the
intraorganic biochemical processes and he gave a sweeping
picture and grand panorama of nutrition (1 12). He
differentiated the plastic from "respiratory" or caloric
food. The plastic food (proteins) build up the tissues
of the body, while the caloric food (fats and carbohydrates) are oxidized to carbonic acid and water,
whereby animal heat is produced (113). The animal
organism is incapable of producing organic compounds
from inorganic substances (water, carbonic acid, ammonia) like the plants do; but it is able to transform food
into the "more highly organized matter", into the complex constituents of the brain (1 14). The proteins — all
derived in the last instance from vegetable compounds —
build up the blood and solid tissues of the body. The
ultimate metabolic products of the proteins are urea
and uric acid. The amount of urea excreted into the
urine represents the measure of metabolic activity (115).
The vital force is a necessary condition to build up
muscular proteins which are devitalized to urea in a
chemical process which generates the mechanical force
of the muscles (116). These considerations of Liebig
led A Helmholtz to investigate the relation between
chemical processes and muscular activity; it was the
origin of his studies on energetic transformations
culminating in his early monograph 'On the Conservation of Force" (1 17).
In his critical appraisal ofLiebig's energetic doctrine
/. R. Mayer elucidated the question of the source of
J. Clin. Chem. din. Biochem. / Vol. 19, 1981 / No. 6
In the late forties Cl Bernard examined the problem
of the origin of animal sugar (119). The point of
departure was the following consideration:
1) The blood of animals fed with starch or saccharine
substances contains sugar.
In 1853 Bernard published a comprehensive monograph
entitled New Function of the Liver Considered As An
Organ Producing Sugar in Man and Animals (121). The
liver he stated, exerts two functions. It secretes bile and
it produces sugar. The liver is a chemical laboratory, the
central metabolic instrument of the animal organism; in
the liver the elements of blood, sugar, bile and alimentary
substances combine and separate in a thousand ways
(122). In 1854/55 Bernard found a substance in the
liver parenchyma which could be split into sugar in a
fermenting process and which he named "glycogenic
substance" or animal starch (123). In 1857 (124) he
isolated this "glycogenic substance" in pure form and
characterized it as a polysaccharide which could be
split into sugar by mineral acids, pancreatic juice and
amylase. The glycogenic substance, Bernard stated, is
produced from proteins in the liver parenchyma; it is
transformed in to sugar by the action of a liver ferment,
and the sugar is then released into the blood-stream in
a process termed "internal secretion" by Bernard (125).
Clinical Chemistry
The conviction that the physico-chemical causality
pervades dead and living nature, the discoveries of new
substances in the healthy and diseased body, the development of organic and physiological chemistry led to a
first wave of clinical chemistry in the late thirties and in
the forties of the nineteenth century.
318
George Owen Rees wrote a treatise on the analysis of
blood and urine in health and disease (126), Julius Vogel
published an Introduction to the Use of the Microscope
for Zoochemical Analysis (127). Johann Franz Simon
published his Handbuch der Medizinischen Chemie in
1840 and 1842, later also appearing in english translation: Animal Chemistry with Reference to Physiology
and Pathology of Man (128). The first periodical dealing
exclusively with pathological chemistry was Heller's
Archive for Pathological Chemistry and Microscopy
(since 1844) (129). Vienna!s renowned pathologist
CarlRokitansky emphasized the importance of
chemistry in pathological research. In Rokitansky's
pathology the blood formed a central role. While the
organized elements of the blood, the globules and fibrin
are the subject of morphological investigation, the chemical changes and alterations of the non organized substances of the blood belong to the chemical part of
pathology (130). Chemistry thus extends the range of
pathological methods.
Mani: The historical background of Clinical Chemistry
3) Pharmacodyriamics which studies the absorption, action and elimination of drugs.
Pathological chemistry, Simon stated, emerges from medicine as its mother-discipline. The art of healing has to
transcend a merely empirical state, it has to exhaust the
"rich well" offered by the sciences.
Urine Analysis (134)
Urinary pathology, Simon underlined, is the most important field of pathological chemistry. A dark red or brownred color indicates the presence of blood or of bile pig^
ments. A first clue can be drawn from the specific weight
and from the reaction of urine. Limpid clear urine of high
specific weight can point to diabetes confirmed by the
sugar test (135). A sediment of acid urine can consist of
uric acid, urates, calcium oxalate, while a sediment of alkaline urine may be due to phosphates of alkaline earth
metals. The microscopic observation of sediments demonstrates the characteristic crystal shape of cystine, calcium oxalate or magnesium ammonium phosphate (136)
Let me mention two early clinical chemists who endeav- Organic sediments can consist of blood or pus corpuscles.
ored to apply chemistry in a systematic way to clinical
In Bright*s disease Simon discovered tubules or cylinders
medicine: Johann Franz Simon (1807—1843) in Berlin
(137). The two most important pathological substances
and Johann Florian Heller (1813-1871) in Vienna (131). present in urine are albumin and glucose. Albuminous
Simon started his career as a pharmacist, then the studied urine is an important sign ofBright's disease. In cases of
chemistry and took his Ph. D. in 1838 with a study on
scarlet fever albuminous urine points to a kidney affecmother's milk, and became Privatdozent for chemistry
tion. In patients suffering from thirst and "hydruria"
in 1842. From the beginning of his research career he
one has to search for glucose in the urine to confirm the
dealt with problems of pathological chemistry and he
diagnosis of diabetes mellitus (138).
wanted to establish a chemical laboratory attached to
Another early clinical chemist was Johann Florian Heller
the department of medicine at the Charite hospital in
(1813-1871) native from Iglaü in Moravia (139). He
Berlin. Despite the support of Johann Lucas Schoenlein
took his Doctor of Chemistry at the University of Prague
and the influential Alexander von Humboldt, his plan
in 1837, studied with/. Liebig and F. Wöhler and moved
did not materialize. In his Animal Chemistry and in the
to Vienna where he established a laboratory of pathologifirst volume of his periodical: Contributions to Physiocal chemistry in the Allgemeines Krankenhaus. His long
logical and Pathological Chemistry (continued afterfight extending over a decade to be officially appointed
wards as Heller's Archiv) Simon outlined the following
as head of the Patho-Chemisches Institut reflects the critask of pathological chemistry (132).
tical attitude of the medical faculty of Vienna towards
1) A precise chemical characterization of animal subhis person, and a basically favorable but reserved attitude
stances.
towards the role and significance of pathological chemistry for clinical medicine (140).
2) The investigation of the physical and chemical
behavior of organic fluids and solids
3) For each substance the following data should be
ascertained: the occurrence, isolation in pure form,
reactions of the humors and solids of the body with
chemical reagents, empirical formula.
4) The determination of the quantity of physiological
and pathological substances
5) Demonstration of specific morbid substances in the
humors.
Scientific medicine has to comprise the following areas
(133):
1) Physiological chemistry and microscopy
2) Pathological chemistry and microscopy
Heller's program of clinical chemistry
POT Heller the basic pillars of modem medicine were
(141): Physical diagnosis, pathological anatomy and pathological chemistry and microscopy. The patho-chemical laboratory must be situated in the hospital. The problems emerge from the wards, from the bed-side. The substratum of the pathological chemist are the bodily fluids
and solids which are submitted to chemical analysis. Mecal chemistry and microscopy deals with the following,
areas and problems:
1) The chemical and microscopic identification and characterization of pathological products of the bodily humors and solids
J. Clin. Chem. Clin. Biochem. / Vol. 19,1981 / No. 6
Mani: The historical background of Clinical Chemistry
2) The investigation of the secretory and excretory substances in health and disease
3) Analysis of the excretory products after medication.
319
nature and properties of fatty bodies of the blood have
not be determined; the proteins of the blood cannot be
characterized properly; fibrin as a most important substance cannot be isolated in pure form; Apart from all
these shortcomings there remains the basic fact that the
metabolic processes in health and disease are practically
unknown.
The indispensable requirements of pathological chemistry are: medical knowledge and chemical competence.
Clinical chemistry must devise tests easy to perform. The
best known test developed by Heller was his "Ringprobe"
detecting albumin in the urine by means of adding nitric The critical statement of Lehmann was borne out by the
acid (142).
further development of clinical chemistry. Heller's ArAnother important representative of early clinical chemis- chiv ceased to appear after the sixth volume. There were
try was the physician and chemist Johann Joseph Scherer not enough original papers and competent contributors,
(1814-1869) (143). After his medical training he studied there were already other journals publishing papers dealing with clinical chemistry, e. g. The Annalen of Liebig,
chemistry in Liebig's laboratory at Giessen (144) and
the Annales de Chimie, Mullens Archiv, the Zeitschrift
established afterwards a "Clinical Chemical Laboratory"
für rationelle Medizin, the Archiv für Physiologische Heilat the University of Würzburg devoted to pathological
kunde etc. But above all in the 1840's and 1850's clinichemistry (145). In 1843 he published the first results
from his laboratory working in connection with the Juli- cal chemistry had no solid biochemical basis. The occurrence of cystine in the urine was an isolated fact before
us Hospital in Würzburg (146).
the notion of amino acid was established. The evaluation
In the second edition of his Textbook of Physiological
of glucosuria became significant when it was related to
Chemistry C. G. Lehmann of Leipzig gave a critical aphyperglycemia
and the conditions of carbohydrate metapraisal of the state of pathological chemistry (147). The
bolism.
chemist examining pathological products should base his
chemical analysis on clearly defined pathological conditions, if possible on distinct clinical entities. Unfortunately this rule is rarely observed.
The basic shortcoming of pathological chemistry is the
lack of a reliable biochemical foundation applicable to
pathology and clinical medicine. Zoochemistry has not
yet developed reliable methods of blood analysis. The
mineral constituents of the blood are little known; the
After an optimistic decade of pathological chemistry situated between 1840 and 1850 the interest of biochemical research turned to the problems of pure physiological chemistry. F. Hoppe-Seyler, C. Voit, E. Pflüger, W.
Kühne and many others represent the new orientation
towards basic research, while the clinical laboratories
functioned as appendices of clinical medicine with an immediate and practical goal of diagnostic application.
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will be published as a medical thesis of the University of
Bonn by /. Schmalhofer.
Lesky, E. (1965) Die Wiener Medizinische Schule Im
19. Jahrhundert, Böhlau, Graz, Köln pp. 252-254. There
is also an Engl. transl.:
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der Urate, der Knochenerde und einer Eigenthümlichen
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147. Lehmann, C G. (1853) Lehrbuch der Physiologischen
Chemie, 1. Bd. 2. Aufl., Engelmann, Leipzig, p. 5-8.
Prof. Dr. N. Mani
Medizinhistorisches Institut
der Universität
Sigmund-Freud-Straße 25
D-5300Bonnl
J. Clin, Chem. Clin. Bioehem. / Vol. 19,1981,/ No. 6