Clinical Chemistry 47:12
2166 –2178 (2001)
History
Early Blood Chemistry in Britain and France
Noel G. Coley
I review here key research in the early years of the field
of blood chemistry. The review includes successes and
limitations of animal chemistry in the critical period of
the eighteenth and nineteenth centuries. Eighteenth
century medical theories emphasized the primacy of
body solids. Body fluids were governed by the tenets of
humoral pathology. After Boerhaave sparked interest in
the chemistry of the body fluids, a new humoralism
developed. With the rise of animal chemistry in the
eighteenth century, two complementary ideas came into
play. The concept of vital force was introduced in 1774,
and the chemical composition of animal matters, including the blood, began to be investigated. In the early
nineteenth century, the development of new methods of
analysis encouraged such chemical studies. Prominent
chemists led the field, and physicians also became
involved. Physiologists were often opposed to the chemical tradition, but François Magendie recognized the
importance of chemistry in physiology. Liebig linked
the formation and functions of the blood to general
metabolism and so extended the scope of animal chemistry from 1842. About the same time, microscopic studies led to discoveries of the globular structure of the
blood, and Magendie’s famous pupil, Claude Bernard,
began the animal chemistry studies that led him to new
discoveries in hematology. This review addresses discoveries, controversies, and errors that relate to the
foundations of clinical chemistry and hematology and
describes contributions of instrumental investigators.
© 2001 American Association for Clinical Chemistry
The British Account: Blood and Other Body Fluids
Throughout the eighteenth century, most physicians
thought that diseases arose solely in organs and tissues,
the solid parts of the body. By the last quarter of the
century, solidism was firmly entrenched in medical theory. Body fluids were not thought capable of causing or
Honorary Visiting Research Fellow, The Open University, Milton Keynes,
United Kingdom.
Address for correspondence: 24 Kayemoor Road, Sutton, Surrey SM2 5HT,
England. E-mail [email protected].
Received March 28, 2001; accepted September 10, 2001.
harboring diseases, their possible involvement in pathology was largely ignored, and any changes in them that
might be observed were regarded as symptoms, rather
than causes of disease. According to ancient humoral
doctrine, body fluids, or “humours”, were maintained in
an internal balance. Their relative quantities were considered important, and medical treatments aimed to restore
the balance of these humours when it became disturbed
by sickness. Thus, purging, vomiting, cupping, venesection, and leeches figured prominently in the armory of the
eighteenth century physician.
Blood—preserver of life and vitality—was the most
important of all body fluids (1 ). Mystical properties were
often attributed to blood, and some ascribed its lifepreserving powers to its fluidity. Those who held that
body fluids, unlike organs, did not possess vitality opposed this notion but accepted that blood was different
from other body fluids. The functions of organs such as
the liver, lungs, digestive organs, and brain were thought
to depend on vital spirits conveyed to them by the blood.
a vital force
From the 1770s, some physicians began to focus on animal
chemistry (2 ), analyzing animal substances and studying
vital functions such as respiration and digestion. As it
became clear that these vital functions involved complex
chemical transformations that could not be replicated in
the laboratory, it seemed that forces unknown to inanimate matter must control the chemistry of life. To describe
these forces, Friedrich Casimir Medicus (1736 –1808) introduced the term Lebenskraft, or “vital force”, to animal
chemistry in 1774.
The notion of vital force received support in 1796 when
Johannes Reil (1759 –1813) included it as one of five types
of force in nature (3 ). By the end of the century, however,
Reil had become convinced that vital functions would
ultimately be explained in chemical terms and that the
idea of vital force could be discarded. Nevertheless, the
concept of vitalism had gained a following among physiologists and chemists that ensured its use well into the
nineteenth century (4 ). It was invoked to account for the
functions of living organs and tissues, the “organized”
parts of the body. Although doubts remained about
whether blood should be considered an organized fluid,
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Clinical Chemistry 47, No. 12, 2001
there could be no question that blood was essential for the
maintenance of life, and it was generally thought to
possess special vital properties (5 ).1
The New Humoralism
boerhaave’s groundwork
In eighteenth century Britain, many physicians were
educated at Edinburgh, or at Leiden in Holland where
Hermann Boerhaave (1668 –1738) (6 ) was the leading
teacher of chemistry and medicine. Boerhaave based his
chemistry on Newtonian physical principles. Like Albrecht von Haller (1708 –1777), the great Swiss physiologist, Boerhaave eschewed the generalities of vitalism and
preferred physico-mechanical explanations of the vital
functions (7 ).2 For Boerhaave, fluids and solids were
merely different states of matter; the body fluids were just
as important as the solids. Moreover, recognizing the
value of chemistry in clinical and pathologic observations,
he used the chemical analysis of body fluids to aid
diagnosis. Thus, Boerhaave prepared the ground for the
rise of a new form of humoralism, one in which the
chemical composition of body fluids in health and disease
would figure prominently (9 ). Many of his students
achieved important medical positions (10 ), and those who
favored his new ideas were not slow to promote them.
cullen’s nerves
Not all were convinced by Boerhaave’s arguments, however. One such was William Cullen (1710 –1790) (11 ), who
has been regarded as second only to Boerhaave himself as
a teacher of chemistry and medicine. At Edinburgh,
Cullen adopted a sophisticated chemical philosophy and
disagreed with Boerhaave’s emphasis on mechanisms in
explaining the vital functions (12 ). For vital chemistry, he
thought that Boerhaave had paid too little attention to the
influence of the nerves. He argued that morbidity in
organs and tissues caused the nerves to increase the flow
of blood to the affected parts. For Cullen, the blood
became merely an agent, acting under the influence of the
nerves. In keeping with the solidists, he argued that signs
of morbidity in the fluids were symptoms rather than
causes of disease. Cullen’s influence on eighteenth century medicine was strong, but his ideas tended to inhibit
the study of body fluids, and many of his pupils continued to adopt the traditional solidism.
of globules and ferments: a clinical
chemistry– hematology connection
2167
the eighteenth century there were signs of a move toward
a new humoral pathology. For example, in 1839 –1840,
Henry Ancell, surgeon to the Western Dispensary in
London, discussed the rise of fluidism in a historical
survey of the physiology and pathology of animal fluids
given at the school of anatomy adjoining St. George’s
Hospital (13 ). In addition, Richard Davies, a Bath physician writing in 1760 on the value of blood analysis,
identified three of its constituents as serum, “gluten”, and
“red globules” (14 ). George Fordyce (1736 –1802), a physician at St. Thomas’s Hospital, although a pupil and
friend of Cullen, attempted a chemical study of body
fluids. He identified some components of saliva, gastric
juice, pancreatic fluid, and bile, but he was unclear about
the functions of these fluids; e.g., the role of “ferments” in
saliva and gastric juice. His ideas about the formation of
chyle were vague, although he found components in it
reminiscent of blood, including “white globules” and a
coagulable fluid (15 ).3
William Hewson (1739 –1774), a pupil and associate of
William and John Hunter, studied the blood itself. In the
1770s, Hewson, who had attended Fordyce’s chemical
lectures, began to study some of the metabolic changes in
which the blood is involved. He discovered a lymphatic
system in birds and reptiles previously thought not to
possess one, and he accepted William Hunter’s view that
the absorption of nutrients is a function of the lymph
glands. Because the lymphatic system has connections
with blood vessels, it seemed to Hewson that blood must
also be involved in nutrition, and he therefore began to
study the blood itself (16 –19 ).
Hewson examined red globules, which he found in the
serum to be flat rather than globular (20 ), and described
leukocytes (white blood globules), which he observed by
diluting blood with serum instead of water. However, his
most important contribution revealed some essential features of blood coagulation, which he attributed to a
“coagulable lymph”, now known to be the nucleoprotein
fibrinogen. As a result of his discoveries, Hewson has
sometimes been called the father of hematology.4
At the end of the century, James Corrie, an Edinburgh
physician, still suggested that “the humoral pathology so
long discarded may yet [. . .] be revived” (22 ).
The Role of the Animal Chemists in Clinical Chemistry
the nature of blood
As is evident from the foregoing, attempts to understand
the nature and functions of the blood were not confined to
Some British physicians did begin to study the chemical
properties of the blood, however, and in the second half of
1
In a series of public lectures for a general audience at the Gresham
Institution, John Spurgin (1797–1866), physician and medical writer, adopted
the notion of blood as a vital fluid without question.
2
For a fuller discussion of the mechanist-vitalist controversy, see Heim (8 ).
3
Based on Fordyce’s Gulstonian Lecture at the Royal College of Physicians
in 1789. Fordyce’s life and work are reassessed in my paper, “George Fordyce
MD, FRS (1738 –1802), physician-chemist and eccentric”. Notes Rec R Soc Lond
2001;55:395– 409.
4
The word itself was first used in 1743 by the Dutch physician Thomas
Schwencke (1693–1733). The epithet has also been applied to others (21 ).
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Coley: Early Blood Chemistry in Britain and France
medicine alone. Progress also depended on developments
in chemistry as a whole as well as the introduction of new
analytical methods. During the eighteenth century, chemists relied on the theory of phlogiston, but the last decade
of the century saw the introduction of Lavoisier’s theory
concerning oxygen. This led to experimental observations
on respiration that revealed links among oxygen, the
products of digestion, animal heat, and the components of
the blood (23 ).
In the early nineteenth century, chemists introduced
improved analytical techniques to replace the traditional
method of destructive distillation (24 ). Animal substances, including body fluids, became legitimate subjects
for analysis by animal chemists, and the empirical foundations for physiologic and clinical chemistry were laid.
The blood, available in quantity although far from easy
to analyze, was prominent in these studies because it was
thought to be created from the food and to contain the
constituents of all the other components of the body.
Antoine Fourcroy (1755–1809) suggested that chyle was
converted into blood by a process beginning in the
subclavian vein and continuing in the lungs. He argued
that in digestion and assimilation, there must be a stage at
which inanimate food was converted into living matter in
a process that he designated “animalisation” (25 ).
Fourcroy also examined human blood in subjects of
different ages in an effort to relate its fibrous content to
the state of the muscles. He found that in infants, in whom
muscles were weak, the fibrous content of the blood was
low; blood from old men, whose muscles contained more
fibrous matter, had a higher fibrous content (26 ).
Fourcroy also identified three main constituents of animal
tissues—albumin, gelatin, and fibrin— by chemical tests
(27 ).
a place for chemistry in physiology?
Further experimental work on animal fluids was made
possible by new analytical techniques introduced by J.J.
Berzelius (1779 –1848) in Sweden and Justus von Liebig
(1803–1873) in Germany. These methods were improved
by William Prout (1785–1850), the London physician and
animal chemist best remembered for his atomic weight
hypothesis (28 ). All of these analytical techniques involved the oxidation of organic matter to carbon dioxide
and water.
Prout determined the composition of many animal
substances more accurately than any of his contemporaries and investigated the processes of animal nutrition
from the digestion of food to the fabrication of blood (29 ).
He initially thought that digestive juice contained lactic
acid, but he was forced to revise his ideas in 1824 when he
discovered free hydrochloric acid in the stomach (30 ). He
reexamined the digestive processes and, after another 10
years of careful investigation, proposed a general theory
of digestion and assimilation (31 ). Prout was a powerful
advocate of the value of chemistry in physiology (32 ), but
his repeated calls for physiologists to become chemists
were met with strong objections by vitalists who could see
no place for chemistry in the study of the vital functions.5
the chemical composition of animal fluids,
including blood
Animal chemistry attracted attention from other young
physicians, notably the Liverpool physician John Bostock,
the Younger (1773–1846). While investigating the chemical composition of animal fluids, Bostock showed that
albumin could be distinguished from gelatin (33, 34 ). He
found that heat and mercuric chloride coagulated albumin, whereas gelatin liquefied when heated and was
coagulated by tannin (35 ). Gelatin was known to be an
important constituent of animal tissues, and Fourcroy (36 )
had asserted that it occurred in blood serum. When
Bostock added tannin to serum from which the albumin
had been removed, however, he observed no further
precipitation. He therefore concluded that blood did not
contain gelatin (37 ).6 Bostock, studying other chemical
characteristics, attributed the alkalinity of blood to the
presence of free soda (38 ), which was in agreement with
Berzelius and Alexander Marcet (1770 –1828), physician at
Guy’s Hospital. When George Pearson (1751–1828), a
physician at St. George’s Hospital, stated that the alkali
was potash rather than soda, a controversy followed
(39 – 42 ). In 1817, Bostock moved to London, where he
ceased to practice medicine and instead turned to chemistry and physiology. The first of Richard Bright’s collaborators, he later lectured at Guy’s Hospital medical
school, following Marcet in 1820 (43 ).
A need for better information on the chemical composition of animal substances was recognized by Berzelius
in Sweden, and in 1806 –1808 he published a two-volume
textbook of animal chemistry in Swedish (44 ). Humphry
Davy at once realized the importance of the work and
resolved to have it translated into English. The project
seemed eminently suitable for the newly formed Animal
Chemistry Club, a special interest group within the Royal
Society. Unfortunately, mainly for financial reasons, no
English translation of the work was ever published (45 ).
Marcet later persuaded Berzelius to publish some of his
analyses of animal fluids in English, which became an
important source of data for British animal chemists (46 ).
In his analysis of the blood, Berzelius separated the
solid and liquid parts by coagulation and examined each
part separately. In the clot, he found compounds of
carbon, phosphorus, calcium, magnesium, and iron (Table
1). The serum consisted of water containing albumin,
5
Prout’s first call for physiologists to become chemists came in 1816, but
was repeated in his Gullstonian Lectures of 1831. A debate between Prout and
Wilson Philip followed. Wilson Philip argued that chemistry and the science of
the vital functions were so different in kind that study of the one would
seriously affect that of the other.
6
Berzelius later confirmed the absence of gelatin in blood serum.
Clinical Chemistry 47, No. 12, 2001
Table 1. Berzelius’s analysis of blood clot (1812).a
Proportion,
parts per 100
Oxide of iron
Subphosphate of iron
Phosphate of lime and a
little magnesia
Pure lime
Carbon dioxide and loss
Total
a
50.0
7.5
6.0
20.0
16.3
100.0
From Berzelius (46 ).
various salts, and some animal matter. His analysis of the
serum confirmed results obtained by Marcet (Table 2).
Berzelius also found that bile, saliva, mucous fluids, the
humors of the eye, and serous fluids contained the same
salts in roughly the same proportions as in blood serum.
He thought that this result showed that all animal secretions were ultimately derived from the blood. Thus, by
the second decade of the nineteenth century, the new
humoralism had already produced useful observations on
the properties and constituents of the blood.
The New Humoralism in Physiologic Chemistry
chemical properties of blood
By the third decade of the nineteenth century, chemical
changes in blood began to attract the attention of some
physicians. In 1832, George Leith Roupell (1797–1854), a
physician at St. Bartholomew’s Hospital, described chemical changes in the blood of cholera victims in his Croonian Lectures at the Royal College of Physicians in London.
Conscious of the work that had been done on animal
fluids since the late eighteenth century, he said, “it is to a
more exact acquaintance with the chemical changes of the
Table 2. Comparison of analyses of blood serum by
A. Marcet and J.J. Berzelius.a
Marcet
Water
Albumin
Muriate of soda and potash
Muco-extractive matter
Sodium carbonate
Potassium sulfate
Earthy phosphates
Total
Proportion,
parts per 1000
900.00
86.80
6.60
4.00
1.65
0.35
0.60
1000.00
Berzelius
Water
Albumin
Muriate of soda and potash
Lactate of soda and animal matter
Soda and phosphate of soda
Loss
Total
a
From Lecanu LR. Ann Chim 1831;48:316.
905.00
80.00
6.00
4.00
4.10
0.90
1000.00
2169
fluids in diseases that we are chiefly to look for the future
advancement of physic as a science” (47 ). In the same
year, William Stevens (1786 –1868) described changes he
observed in the composition of the blood in fevers,
cholera, and other diseases during his practice as a
physician in the West Indies. Stevens acknowledged
Prout’s contributions to animal chemistry and recognized
blood as the source of secretions, such as bile and gastric
and pancreatic juices, and excretions, such as perspiration
and urine. He also thought that the blood nourished the
solid parts of the body and conveyed gases that it held in
the free state. Despite his belief in the importance of the
chemical properties of the blood, Stevens, like so many of
his contemporaries, remained a vitalist (48 ).
It had long been suspected that the vitality of the blood
was related to its property of coagulation. John Hunter
argued that coagulation occurred under the influence of
the vital force (49 ), and Fourcroy even suggested that
coagulation of the blood might be the mechanism by
which animal fibers were formed in the living body (50 ).
However, because coagulation occurred only after the
blood had left the body, others such as Charles Thackrah
(1795–1833),7 a physician in Leeds, argued that the process resulted from the “loss” of vitality (51 ). In that case,
the vital force in living blood must maintain the fluidity of
blood (52 ).
the scarlet color
The transformation from dark venous to bright arterial
blood as a result of contact with the air was another
puzzling characteristic of this fluid. Because the change
took place mainly in the lungs, it obviously depended on
respiration; it also seemed linked to the production of
animal heat (53 ). [Adair Crawford (1748 –1795) explained
animal heat as the release of phlogiston (54 )]. Comparing
the body to a heat engine, Lavoisier thought that animal
heat was produced in the lungs because of the oxidation
of nutrients in the blood, but Stevens observed that this
could not account for the clinical phenomena of fevers.
Stevens remarked that there was often a cold stage in
fevers during which patients sometimes died. If patients
recovered, heat began first in the extremities, and although the patient still felt cold, the skin might become
burning hot. This convinced him that heat was generated
throughout the body rather than in the lungs alone, and
he suggested that in all warm-blooded animals carbon
combined with oxygen in arterial blood and that animal
heat was “evolved in consequence of the chemical combination of these two agents” (55 ). By the 1840s, it was
widely accepted that the source of animal heat was in the
blood itself, greatest in the lungs where arterial blood is
formed, but proceeding wherever arterial blood meets
oxidizable carbon in the tissues (56 ). Although this is
7
Thackrah later became known for studies of the industrial diseases of his
home town.
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Coley: Early Blood Chemistry in Britain and France
broadly correct, the true origins of animal heat remained
unrecognized throughout the nineteenth century (57 ).
By a strange chance, the color of venous blood led to
one expression of the mechanical equivalent of heat. In
1840, Julius R. Mayer (1814 –1878), a German physician
working on a Dutch ship bound for Java, noticed that
venous blood drawn from European sailors was unusually bright red. He thought the heat of the tropics must
cause a lower metabolic rate, requiring less oxygen than
in a colder climate. Mayer decided that this confirmed the
theory of animal heat from the oxidation of food. Moreover, he suggested that the heat evolved in muscular
exertion must also be derived from the chemical energy
latent in food; the intake of food and the output of “force”
(i.e., energy) must be balanced. After returning home in
1841, Mayer wrote an account of his ideas that was
published by Liebig in his Annalen in 1842, the same year
in which Leibig’s own theories of animal chemistry appeared (58, 59 ).
Others favored different explanations of the color of
blood. Stevens had ascribed the reddening of arterial
blood to the absorption of oxygen. He began to doubt this
when he observed that certain salts also produced the
scarlet color and that oxygen did not cause reddening of
a black clot free from salts. He decided that carbonic acid
turned venous blood dark. When this compound was
removed during respiration, it was not oxygen, but the
saline ingredients in the blood that turned it scarlet (60 ).
It had been known since the mid-eighteenth century,
however, that the blood contained iron, and Fourcroy (61 )
ascribed the red color of blood to a subphosphate of iron,
a view accepted by many chemists. William Charles Wells
(1757–1817), a physician at St. Thomas’s Hospital, attributed the red color of the blood to a peculiar animal
substance (62 ).8 In 1812, William Thomas Brande (1788 –
1866), professor of chemistry at the Royal Institution,
showed that the proportion of iron in the “coloring
matter” of the blood was no greater than that in other
animal substances (64 ). [This was later confirmed by
Vauquelin (65 ).] Thus, although iron was present in the
coloring matter, there was also a large proportion of
animal matter in the blood, a remarkably astute conclusion that the chemistry of the period was incapable of
pursuing. Later, in 1824, Sir Charles Scudamore (1779 –
1849), a fashionable London physician, published a chemical study of the blood (66 ) in which he confirmed
Brande’s observation that the red coloring matter of the
blood was an “animal principle” containing a small
proportion of iron.
ing interest. Sir Everard Home (1756 –1832), a surgeon at
St. George’s Hospital and brother-in-law of John Hunter,
had observed this some years earlier (67, 68 ), but John
Davy (1790 –1868), Humphry Davy’s younger brother,
disputed this (69 ). Scudamore, in 1824, confirmed the
evolution of carbon dioxide, stating that it was “evidently
an essential circumstance in the process of coagulation, as
the same causes which retain the carbonic acid in the
blood, delay coagulation” (70 ). He also mentioned the
possible evolution of heat and extended his investigations
to include the effects of electricity, galvanism, and various
salts and other chemical agents on the process.
Thackrah confirmed the presence of small amounts of
albumin in blood serum, together with mineral salts,
including the carbonate, chloride, phosphate, and acetate
salts of sodium; potassium chloride and potassium sulfate; calcium phosphate; and free alkali. In the clot, he
found three components, red corpuscles, fibrin, and albumin, and observed that the last had often been overlooked.9 He could not confirm the release of heat during
coagulation that had been reported earlier by Gordon (73 )
and John Davy ( 74 ) and concluded that those who
claimed that heat was evolved in the process were mistaken (75 ). He agreed that carbon dioxide was usually
given off, but he was not convinced that this was either a
necessary condition for or a cause of coagulation.
Having decided that none of the substances he had
examined explained the process of coagulation satisfactorily, Thackrah then turned to the effects of the nerves
whose influence on the blood had been suggested by
Cullen, Berzelius, and others. By confining samples of
blood in live leeches and in sections of veins taken from
dead animals, Thackrah found that so long as “irritability” remained, blood contained in such vessels did not
coagulate, although it did so quite rapidly after the loss of
vital force. Stevens agreed with Thackrah that vitality and
the motion of the blood in the living body prevented
coagulation, but he still thought the fundamental cause of
coagulation resided in the chemical changes that occurred
when blood was drawn from the system and exposed to
air (76 ). Thackrah disagreed with Stevens and asserted
that the vital or nervous influence was the source of
fluidity in the blood. The loss of that influence thus
caused coagulation (77 ). Moreover, he argued that the
rate of coagulation of extravasated blood was a diagnostic
indicator of the “vitality” of a patient. These conflicting
views demonstrate the difficulty of achieving certainty in
blood studies in the early years of the nineteenth century.
the beginnings of medical chemistry
clots and conflicts
Scudamore repeated the curious observation that carbonic
acid was evolved during coagulation, a process of increas-
8
According to William Henry (63 ), LJ Thenard (1777–1857) also attributed
the color of the blood to a special animal coloring matter.
Among British physicians of the period, George Owen
Rees (1813–1889), a physician at Guy’s Hospital, was one
9
Compare this with Prout’s On Diabetes (71 ), where albumin was not
mentioned, and Henry’s The Elements of Experimental Chemistry (72 ), which also
failed to mention albumin.
Clinical Chemistry 47, No. 12, 2001
of the foremost champions of the new humoralism (78 ). In
1833, while still a student, he showed that urea could be
identified in diabetic blood serum (79 ). R.H. Brett and
Golding Bird, his colleagues at Guy’s Hospital, disagreed
with this finding (80 ), and a controversy ensued in which
Rees showed a clear grasp of chemical analysis (81 ). Rees
developed his skill as an analyst while assisting Richard
Bright at Guy’s Hospital. Later, as he developed the
chemical analysis of blood and urine, he advocated his
methods as an aid to diagnosis and aimed to simplify
them for the ordinary medical practitioner. He deplored
the lack of interest in the chemistry of the blood shown by
most physicians (82 ). He admitted that although animal
chemistry had developed rapidly, it had not produced the
predicted medical advances, and physicians used this
deficiency to support their lack of interest in chemical
methods. Cheered by renewed interest in blood chemistry, however, Rees said, “The philosophical revival of a
humoral pathology bids fair to render the analysis of
diseased blood one of the most useful adjuncts to our
medical knowledge” (83 ).
Rees based his own analyses on Berzelius’s work, but
he was aware that others, especially Lecanu in France,
had applied new chemical methods to blood analysis.
Rees applauded such efforts, arguing that the chemical
composition of healthy blood should be determined for
use as a comparative guide in cases in which disease
caused noticeable changes. For example, in cholera the
blood contained a lower proportion of water, but in
diabetes there was an excess of fatty matter and urea. In
other cases, cholesterine, the coloring matter of the bile,
was found, but because of inadequate analytic techniques,
these compounds had often been missed altogether. Rees
emphasized the need to determine each constituent of the
serum by a separate procedure and criticized earlier
analysts for attempting to determine all of the constituents by a single analysis (84 ). In 1838, he described a
method for isolating sugar from diabetic blood serum,
which has been hailed as a major contribution to medical
chemistry (85 ).
the microscopic story
In the 1840s, microscopic studies of the blood began to
reveal some new facts. Rees, working with Samuel Lane,
a colleague at Guy’s Hospital, investigated the microscopic structure and properties of red corpuscles. They
found that each red corpuscle was surrounded by a
membrane, and they carried out experiments on the
osmotic effects of various solutions (86 ). At about the
same time, William Addison (1802–1881), a physician in
Malvern not to be confused with his famous namesake,
Thomas Addison, observed “rough or granulated colorless capsules” (granulocytes) and “loose or independent
molecules” (platelets) in the blood (87, 88 ). The value of
microscopy in the study of disease was also recognized by
the French physician Alfred Donné (1801–1878), who
from the early 1840s in Paris, organized classes in clinical
2171
microscopy for physicians (89 ). Some years later, George
Gulliver, assistant surgeon to the Royal Regiment of
Horse Guards, suggested that pus globules, detected in
the blood in cases of extensive suppuration or great
inflammatory swelling, were modified red corpuscles. In
addition, recognizing the value of quantitative studies,
Gulliver measured the diameters of the red corpuscles in
various species (90 ). Gulliver’s quantitative measurements preceded the techniques of blood-cell counting and
hemoglobin estimation (91 ).
controversy prompts research
In 1842, Liebig, having turned his attention from pure
organic chemistry to its applications in agriculture and
physiology, introduced a new approach to the chemistry
of the blood and its role in animal nutrition (92 ). Assuming that the chemical composition of the blood was
identical to that of flesh, Liebig assigned the empirical
formula C48N6H39O15 to both. His chemical account of
physiologic phenomena grossly oversimplified the intricacies of metabolism, and his “equations”, in which
empirical formulas were balanced arithmetically, provided no more than an overall summary of the changes
that they were intended to explain. Like Mayer, Liebig
sought to balance the intake of food against the output of
muscular energy and animal heat (93 ). Mayer accused
Liebig of plagiarism, but it is more likely that the similarities between them were the result of common influences,
although Liebig was a vitalist and Mayer was not. Liebig
agreed with Mayer that the oxidation of carbohydrates
yielded animal heat, but held that the oxidation of muscle
tissue was the source of animal energy. He also thought
that the excreted urea and other nitrogen compounds
resulted from the degradation of muscle tissue and were
a measure of the work done by the animal. He also
discussed the formation of the blood and its function as a
carrier of nutrients and excretory products. Liebig’s ideas,
influential among British animal chemists, provoked controversies between physiologists and chemists that stimulated valuable research into animal metabolism [see
Holmes (94 ), which is an exhaustive summary of the
experimental investigation of Liebig’s theories up to
1870].
the qualitative vs the quantitative
Some found that qualitative data came under fire. Rees
investigated the relationships between chyle, lymph, and
blood, and his analyses led him to agree with those, like
Prout and Liebig, who regarded the formation of blood as
a culminating stage in nutrition and assimilation (95 ).
Rees analyzed chyle taken from the bodies of newly
executed prisoners for Samuel Lane, who had been commissioned to supply an article including this topic for
Todd’s Cyclopaedia of Anatomy and Physiology (96 ). He
found that the fatty matter was similar to that of the
blood, except that the latter contained phosphorus (97 ).
As a result of these observations, he returned to the idea
2172
Coley: Early Blood Chemistry in Britain and France
that chyle might be an intermediate product in the formation of blood, although by this time he had become
suspicious of the suggestion that the incipient reddening
of chyle as it changed into blood could be observed (97 ).10
Five years later, Rees proposed a new theory to explain
the color changes of the blood. He suggested that the red
globules of venous blood contained “phosphorized” fat in
a serum deficient in alkaline phosphates, whereas in
arterial blood the red globules contained no such fats but
the serum was richer in alkaline phosphates. He suggested that the reddening of the blood occurred when
tribasic sodium phosphate formed by the oxidation of
phosphorized fats in venous blood reacted with hematosine. We may see here a hint of later developments
regarding the role of phosphorus in cell respiration.
However, Rees failed to provide quantitative results to
support his new theory, and his assertion that qualitative
observations were sufficient to establish its truth did not
convince his critics. If correct, the theory seemed to imply
that nearly all of the alkaline phosphates formed in
arterial blood must be discharged before the blood
reached the veins. This would necessitate a large constant
supply of phosphorus to the venous blood and a more
copious elimination of phosphates than had hitherto been
suspected.
Rees’s paper was read at a meeting of the Royal Society
on June 3, 1847, and was printed in the Proceedings (98 ).
He was asked to supply more convincing experimental
evidence before the paper could be accepted for publication in the Philosophical Transactions. After testing his
theory further, Rees produced more qualitative observations to support it, but he was unable to demonstrate its
truth beyond doubt.11 The simple tests that had served
him so well in other areas of clinical chemistry, including
his work on the blood, were inadequate to explain the
complex reactions involved in one of the blood’s chief
functions.
At about the same period, a new book on animal (and
human) chemistry by the young German animal chemist
Johann Franz Simon (1807–1843) appeared posthumously.12 Simon adopted many of Liebig’s ideas, including his
use of empirical formulas, his notion of the metamorphosis of tissues, and his “equations” (102 ). He began with
the idea that the blood nourishes cells and organs, supplying them with albumin, fibrin, and fat. The cells would
select appropriate nutritive matter and form decomposi-
10
Even the great German physiologist Johann Müller claimed to have
observed this change in the chyle of a horse, but Rees failed to confirm it.
11
The revised paper was later published in Philosophical Magazine (99 ) and
Erdmann’s Journal für Praktische Chemie (100 ).
12
Simon became a private tutor at the University of Berlin in 1843, but his
death later that year cut short his brief career (101 ).
tion products to be excreted.13 He named urea, bilin, and
carbonic acid among the substances formed by the vital
energy of the blood corpuscles nourished by oxygen,
albumin, and fat, but he thought that the most important
product of the blood was animal heat, released during the
combination of oxygen with the carbon of globulin (104 ).
He thought that the blood conveyed the excretory products either to the lungs or via the kidneys to the urine and
that the quantity of urea excreted was directly related to
the evolved animal heat. Simon’s work, which showed
great promise, was highly regarded by many British
animal chemists; sadly, he died at the age of 36.
The French Version
the beginnings of animal chemistry
In France, animal chemistry developed rapidly after the
introduction of Lavoisier’s antiphlogistic theory.
Fourcroy, assisted by L.N. Vauquelin (1763–1829), investigated many aspects of animal chemistry, including the
nature and properties of the blood. Vauquelin, an outstanding experimental chemist, later worked alone and
produced several hundred papers on chemical topics,
many of which were linked to animal and physiologic
chemistry (105, 106 ). Animal fluids such as blood and
urine were examined, but physicians largely ignored this
chemical research. In France, as in Britain, medical theorists emphasized the importance of the organs and tissues,
and by the last quarter of the eighteenth century, solidist
theories of disease were firmly entrenched in French
medicine.
In Paris, François Joseph Victor Broussais (1772–1838)
and his follower Jean Baptiste Bouillaud (1796 –1881),
proponents of a system called “physiological medicine”,
regarded the gastrointestinal organs as the chief seat of
disease (107, 108 ). René Théophile Hyacinthe Laënnec
(1781–1826), inventor of the stethoscope, focused attention on the heart, lungs, and thoracic organs in a system
designated “pathological anatomy”. At Montpellier, however, diseases were regarded as the cause rather than the
effect of pathologic changes in the organs.
By the early nineteenth century, some French physicians, like their British counterparts, began to develop an
interest in the chemical composition and properties of
animal fluids. In the 1820s, Jean Baptiste Dumas (1800 –
1884) and Jean Louis Prévost (1790 –1850) studied the
blood of various animals in relation to vital phenomena
such as respiration and digestion (109, 110 ). In a mainly
physiologic study, they were concerned with the shape,
size, and contents of the red globules and the effects of
various diseases on them. Like Wells and Brande earlier,
they concluded that the coloring matter of the blood
consisted of an animal substance, possibly albumin, combined with iron peroxide.
In 1833, the pharmacist Félix Henri Boudet (1806 –1878)
13
Rees had also compared the analysis of blood with that of urine (103 ).
2173
Clinical Chemistry 47, No. 12, 2001
decided that a more precise chemical analysis of the blood
was needed (111, 112 ). He discarded ill-defined terms
such as “osmazome” and “muco-extractive matter” for
constituents of the serum. Suspecting that the quantities
of many constituents of the blood were very small, Boudet
thought it necessary to examine large volumes of serum to
reveal more detail about its composition (113, 114 ). By
evaporating a large volume of blood to dryness, he was
able to extract small translucent, noncrystalline plates
from the residue. He considered this a new constituent of
blood and named it “seroline”. Its quantity was very
small, but from this residue he extracted a white, alcoholsoluble substance, which he suspected to be cholesterine.
Although Prosper Sylvain Denis (1799 –1863) (115, 116 ), a
physician at Commercy, stated that he had found cholesterine in diseased blood (117 ), Boudet thought that Denis’s crystalline product was probably a phosphorylated
fat crystallized in a form resembling cholesterine (114 ).
the solid foundations of blood chemistry
Louis René Lecanu (1800 –1871) (118, 119 ), professor of
pharmacy at L’École de Pharmacie in Paris, also studied
the chemistry of the blood in the 1830s. Whereas Boudet
had concentrated on serum, however, Lecanu began with
the red coloring matter, for which he adopted Chevreul’s
term “hematosine” (120 ) (Table 3). The compound of
hematosine and albumin found in blood globules he
called “globuline” to distinguish it from hematosine itself.
Uncertainty about the chemical nature of the coloring
matter of the blood led Lecanu to devise fresh experiments on globuline in which he confirmed the presence of
iron. From many comparative analyses, he concluded that
the proportion of water in the blood varied with sex, age,
and temperament (121 ). The proportion of water was
higher in male than in female blood, but for individuals of
the same sex this proportion remained roughly the same
between the ages of 20 and 60. He also found that the
proportion of albumin was about the same in male and
female blood and in individuals of different ages and
temperaments but that the number of globules varied
with sex and age. He found more globules in male than
female blood and more in younger than older individuals
of the same sex. Lecanu’s experiments are the earliest
comparative analyses of healthy blood (122 ). He submitted his observations for an MD degree in the Faculty of
Medicine of the University of Paris in 1837 (123 ).
About the same time, Denis published an analysis of
human blood in which he described seven groups of
components (124 ) (Table 4). He found the properties of
hematosine different from those of albumin and therefore
separated the two compounds. This view was in contrast
to that of Berzelius, who grouped hematosine with albumin and fibrin as albuminous substances. Denis made a
thorough study of the fibrin of the blood (125 ) and found
that it was dissolved in the blood and solidified only on
coagulation, although others considered fibrin to be a
solid constituent of blood globules even before coagulation. Lecanu stated that fibrin lost four-fifths of its weight
on desiccation (Berzelius had said three-fourths), but
Denis found that fibrin took up variable proportions of
water in the presence of salts, such as barium chloride,
potassium nitrate, sodium sulfate, or potassium sulfate,
that held it in solution. He criticized Lecanu for adopting
an error attributable to Chevreul, who thought that chlorides and some other salts formed weaker compounds
with fibrin. Denis further showed that there was no
gelatin in the blood, in spite of its abundance in all the
body tissues and suggested that blood albumin changed
into gelatin as it entered the tissues and organs (126 ). He
found cholesterine absent from healthy blood and showed
that fibrin and albumin had almost identical chemical
properties, an observation later confirmed by Liebig. In
1856, Denis added globulin as a constituent of blood
(127 ). He found the properties of globulin very different
from those of fibrin, with which it was combined. He also
described the presence of globules of chyle and lymph in
blood, as well as the red and white globules.
the apogee
Boudet, Lecanu, and Denis had placed blood chemistry on
a sound foundation, but important as their discoveries
were, it was Gabriel Andral (1797–1876) who brought the
subject to its apogee in the mid-nineteenth century. First
appointed to the Chair of Hygiène in the Faculty of
Medicine at Paris in 1828, Andral became professor of
“pathologie interne” in 1830 and followed Broussais as
professor of general pathology in 1839 (128 –130 ). Two
important early works in which he compared the composition of the blood directly with the solid parts of the body
brought him rapid recognition (131 ). In his studies, he
combined microscopic with chemical procedures. Although at first he was a follower of Broussais’s system of
Table 3. Summary of Lecanu’s analyses of blood.a
Whole blood
Serum
Globules
Total
a
Proportion,
parts per 1000
869.1547
130.8453
1000.00
From Lecanu LR. Ann Chim 1838;67:64 –5.
Serum
Water
25 mineral and
organic substances
Albumin
Total
Proportion,
parts per 1000
Globules
790.3707
10.9800
Fibrin
Hematosine
67.8040
869.1547
Albumin
Total
Proportion,
parts per 1000
2.9480
2.2700
125.6273
130.8453
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Coley: Early Blood Chemistry in Britain and France
Table 4. Components of human blood according to
Denis (124 ).
Fluids and gases
Globules
Albuminous substances
Coloring matter
Fatty matter
Odorous matter
Saline matter
Imponderables
Water, oxygen, carbon dioxide,
nitrogen, and so forth
Red, white, chyle, and lymph
Fibrin and albumin; globulin
Hematosine, yellow biliary matter,
blue matter
Cerebrine, seroline, cholesterine,
fatty acids
Alliaceous matter
Alkalis, soluble salts
Electricity, heat
physiologic medicine, his clinical observations at the
hospital of La Charité in Paris led him to oppose it and
join the partisans of pathologic anatomy. In his Précis
d’Anatomie Pathologique (132 ), he began to set out a new,
more scientific approach to the study of disease.
Andral derived his belief from the system of pathologic
anatomy and his notion of lesions of the blood from Jean
Cruveilhier (1791–1874), who embraced the system in
1829 (133, 134 ). Andral recognized a direct comparison
between the pathology of the blood and that of the organs
and tissues and distinguished between medical theories
based on the primacy of organic lesions and those depending on physical changes in the humors. He also
urged the chemical analysis of the blood, especially in
morbid conditions, and justified the revival of humoralism by asserting that the solids of the body and the blood
were complementary parts of a single whole. He discussed the role of the blood in plethora, anemia, pyrexia,
and so-called organic diseases such as cardiac hypertrophy. Unlike Cruveilhier, who held that phlebitis dominated all pathology (135 ), Andal did not exaggerate the
role of the blood in pathology. Like Alfred Donné (1801–
1878), who observed blood platelets in 1842, Andral relied
heavily on microscopic observations at a time when many
of their contemporaries viewed such observations with
suspicion and regarded the microscope as an amusing toy
rather than a scientific instrument (136 ). In 1835, Andral
reviewed the work done on the blood in France in a joint
article with C.P. Forget (1800 –1861), a professor of clinical
medicine at Strasbourg, that appeared in the Dictionnaire
de Médécine et de Chirurgie Practique (137 ).
pioneering experimental medicine
While Andral and his medical colleagues were studying
blood in relation to disease, François Magendie (1783–
1855), the pioneer of experimental physiology, was similarly engaged. In 1837–1838, he gave a course of lectures
at the Collège de France on blood and the changes it
undergoes in disease; Magendie’s lectures were reported
in full in The Lancet (138 ). He was critical of contemporary
medical theories such as pathologic anatomy (supported
by Andral and Cruveilhier) and solidism; he also expressed contempt for vitalism. Instead, he proposed to
use organic chemistry, “feeble though its light may be”
(139 ), to discover the composition of the blood and
investigate the manner in which morbid changes are
produced. He advocated the study of animal chemistry,
and although he recognized that the subject had yielded
very little new knowledge, he believed that it would come
to exercise great influence on physiology (140 ).
In his own work he combined chemical experiments
with vivisection. Calling his approach “experimental
medicine”, he insisted that most problems associated with
the causes and mechanisms of disease were connected
with the chemical, physical, and vital properties of the
blood. Magendie remarked that his former pupil P.S.
Denis “has made some very curious researches on the
chemical composition of the blood; among other important facts it would appear to result from his labours that
the fibrin is nothing more than albumen combined with
different salts” (141 ). Although Magendie decided to
reserve his judgment on Denis’s findings, he admired the
careful experimental approach and always avoided reliance on systems or “hasty hypotheses”. Thus, Magendie’s
physiologic work supported Andral’s medical approach
to blood studies.
animal chemistry, clinical chemistry, and
medicine
In 1840, Andral, with his colleague Louis Denis Jules
Gavarret (1809 –1890), published quantitative studies of
the composition of the blood (142 ).14 Their work showed
the value of animal chemistry as a means of confirming
diagnoses. Although there were objections to their methods and doubts were raised about accuracy, they stoutly
defended themselves (145 ). They showed that the composition of the blood varied in different pathologic conditions. For example, in fevers they found no increase in
fibrin; in serious cases there was a noticeable decrease, but
in inflammation they observed a definite increase (146 ).
This discovery was an important one confirming the
distinction between these conditions. Andral insisted that
experimental observation was the only sound basis for
advance and thought that progress in hematology would
be made only “when the blood of a great number of
patients shall have been submitted both to a chemical
investigation, and that by the microscope” (147 ). These
ideas were extended to animals when Henri-MamertOnésime Delafond (1805–1861), professor of physiology at
the veterinary college at Alfort, joined Andral and Gavarret to perform experiments on animal blood (148 ).
These studies showed that the composition of the blood
varied in different animals and in humans under different
conditions.
Andral’s discoveries were important, not least because
he provided experimental evidence to confirm them
14
Chauffard (143 ) claims that this work marked the birth of modern
hematology. For information on Gavarret, see Fruton (144 ).
Clinical Chemistry 47, No. 12, 2001
(149 ).15 He brought an objective approach to the study of
disease and placed the new humoralism on a scientific
basis that recognized the importance of chemical analysis
as a means of confirming clinical observations. His concept of “lesions of the blood” supported the notion that
body fluids are as important in pathology as tissues and
organs. By the 1840s, the medical value of blood chemistry was beginning to be recognized, and the foundations
of modern hematology had been laid (151 ). Animal
chemistry had shown both its potential and its limitations
for the improvement of medicine, and with the rise of
animal chemistry the importance of clinical chemistry was
also realized.
7.
8.
9.
10.
11.
the milieu intérieur
In the 1840s, Magendie’s famous pupil Claude Bernard
(1813–1878) turned his attention to animal chemistry
(152 ). As he studied the problems of nutritional processes,
he discovered details about the composition and functions
of the blood. Bernard believed that the vital processes
occurred at the sites where the blood and tissues interacted. He wanted to determine these minute changes as
they occurred, whereas chemical analysis was capable
only of deducing the overall changes that had transpired
during nutrition. He began to realize that chemical analysis was not yet precise enough to detect minute changes
in the blood as it interacted with the tissues. In the 1840s,
his aims were unattainable. Two decades of careful experimentation and deduction led him to the important concept of the milieu intérieur (1865). According to this concept, the blood, as it bathes all the cells and tissues of the
body, creates an internal environment in which nutrients
and oxygen are transferred from the blood to the cells and
waste products are removed from them. Thus, the notion
of blood as an agent and carrier was extended. Bernard’s
grand concept was beyond the understanding of most of
his contemporaries, however, and detailed exploration of
its implications would have to await developments in
twentieth century biochemistry.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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