Bernard disbelieved Pasteur’s definition of a ferment as “a living form originating from a germ”.

Kühne was one of the people who introduced the term “enzyme”. He wrote, "Um Missverständnisse vorzubeugen und lästige Umschreibungen zu vermeiden schlägt Vortragender vor, die ungeformten oder nicht organisierten Fermente, deren Wirkung ohne Anwesenheit von Organismen und ausserhalb derselben erfolgen kann, als Enzyme zu bezeichnen..." (p.190). [In order to avoid misunderstandings and tiresome paraphrases, the lecturer proposes to call the unformed or unorganized ferments, whose action can take place without the presence of organisms and outside them, enzymes....]

Hoppe-Seyler, one of the greatest of the physiological chemists, founded the Zeitschrift für physiologische Chemie and wrote a classical textbook on the subject.

Among the many important contributions of Kossel was his study of the chemistry of the cell and cell-nucleus. Kossel correctly concluded that the function of nuclein is neither to act as a storage substance nor to furnish energy for muscular contraction; rather, it must be associated with the formation of fresh tissue, i.e. the production of proteins.

In 1910 Kossel was awarded the Nobel Prize in Physiology or Medicine "for his research in cell biology, the chemical composition of the cell nucleus, and for his work in isolating and describing nucleic acids."

Kjeldahl, a Danish chemist, devised a method of determining the amount of nitrogen in an organic compound (“Kjeldahl’s method”). A German translation is in Z. anal. Chem., 1883, 22, 366-82.

Isolation of (ß-oxybutyric acid. (Title of second paper: Beiträge zur Kenntniss der activen ß-Oxybuttersäure).

Brieger isolated and determined the composition of a number of the ptomaines.

Van’t Hoff stated that osmotic pressure is proportional to the concentration if the temperature remains invariable, and proportional to the absolute temperature if the concentration remains invariable.

Second edition in English. Matthew Hay devised a test for the determination of bile acids in the urine, published in vol. 1, p. 381.
Digital facsimile from the Hathi Trust at this link.

Jaffe’s creatinine test.

Atlmann coined the term "nucleic acid", replacing Friedrich Miescher's term "nuclein" when it was demonstrated that nuclein was acidic.

Berthelot showed that bacteria acting in clay soils are able to fix nitrogen.

Drechsel discovered that the protein molecule contains both mono and di-amino acids.

Destruction of sugar in the blood.

Hopkins’s method of estimating uric acid in urine.

See No. 702.

Discovery of cell-free fermentation, the turning point in the study of enzymes. 

In 1907 Buchner was awarded the Nobel Prize in Chemistry "for his biochemical researches and his discovery of cell-free fermentation."

Kossel forecast the polypeptide nature of the protein molecule.

Demonstration of the reversible action of lipase.

Isolation of tryptophan.

Includes an account of all the methods of determining osmotic pressure.

Chemical distinction between DNA and RNA. Levene elucidated the fundamentals of nucleic acid chemistry. His work led to the tetranucleotide hypothesis.

Bohr, Hasselbalch, and Krogh showed, in the experimental animal, that the affinity of blood for oxygen depends upon carbon dioxide pressure. This became known as the Bohr effect, though the discovery may have been made by Krogh. English translation in No. 1588.16.

ß-oxidation theory.

In a series of papers, Fischer showed that animal and vegetable proteins are composed of a series of amino-acids united by elimination of water.

Demonstration of the presence of amino-acids in the blood.

Demonstration of the importance of tryptophan in diet. The pioneer work of Hopkins led eventually to the discovery of vitamins.

Explanation of the production of lactic acid in normal muscular contraction.

See No. 735.

Dakin’s oxidation theory.

Hygienic Laboratory.- Bulletin No. 59. December, 1909.  Digital facsimile from the Internet Archive at this link.

Folin introduced several micro-methods for the determination of nitrogen, urea, creatine, etc.

Hemodialysis. See also No. 1976. Preliminary communication in Trans Ass. Amer. Phycns., 1913, 28, 51-4.

"Together with L.G. Rowntree and B.B. Turner, Abel devised what they called a "vividiffusion" apparatus, consisting of a series of tubes surrounded by fluid. They first demonstrated the apparatus at the Physiological Congress in Groningen in 1914.^[9] By allowing arterial blood to enter at one end of the connection, and later return to circulation through the venous connection after dialysis, they were able to demonstrate the existence of free amino acids in blood. By isolating these amino acids from blood circulation, Abel conducted various subsequent researches on the structure of proteins in the blood. Not only did Abel use the apparatus for his research work, he also realized the great clinical potential such dialysis machine would have on managing the damaging effects of renal failure.^[10] The vividiffusion apparatus Abel devised is the precursor to the modern day dialysis machine" (Wikipedia article on John Jacob Abel, accessed 08-2017).

Henderson-Hasselbalch equation for the determination of pH concentration in the blood. English translation in No. 1588.16. For Henderson's papers see No. 9645. 

Ribonudease.

Isolation of glutathione.

Records an important advance in the knowledge concerning the conversion of blood calcium into the insoluble calcium of bone.

Jackson demonstrated the existence of pentose nucleotides in normal blood.

Discovery of adenosine-5′-triphosphate (ATP).

Citric acid cycle (CAC) of aerobic carbohydrate metabolism (Krebs cycle). Three months after his initial publication on CAC Krebs published a supplementary paper aimed at the medical audience, rather than the biochemical audience that read Enzymologia:  "The intermediate metabolism of carboyhdrates," Lancet, 230 (1937) 736-41.

In 1953 Krebs shared the Nobel Prize in Physiology or Medicine with Fritz Lipmann (No. 751.3) "for discovery of the citric acid cycle."

(Thanks to Juan Weiss for recommending the supplementary paper.)

Cohn invented fractionation of plasma proteins, also called blood fractionation. (Order of authorship in the original publication: Cohn, Oncley, Strong, Hughes, Armstrong.) Digital facsimile from PubMedCentral at this link.

Lipmann shared the 1953 Nobel Prize in Physiology or Medicine for his discovery of coenzyme A, an important catalytic substance involved in the cellular conversion of food into energy. He first described the discovery in his paper entitled "Acetylation of sulfanilamide by liver homogenates and extracts," Journal of Biological Chemistry 160, 1945. See No. 14284. In the above paper (No. 751.3) Lipmann isolated the new co-factor and named it coenzyme A.

In 1947 Carl Cori and his wife Gerty Cori (1896-1957) shared the Nobel Prize (with Houssay) “for their discovery of the course of the catalytic conversion of glycogen.”  They are more often remembered for the Cori cycle (see No. 12327).

Ochoa shared the Nobel Prize with Arthur Kornberg in 1959 for their artificial synthesis of nucleic acids by means of enzymes. Order of authorship in the original publication: Ochoa, Grunberg-Manago, Ortiz. See also Ochoa, Severo, "Biosynthesis of ribonucleic acid," Spec. pub. of N.Y. Acad. Sci, 5, 1957, 191-200.

In 1959 Kornberg shared the Nobel Prize in Physiology or Medicine with Severo Ochoa "for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid."

Order of authorship in the original publication: Bessman, Kornberg, Lehman, Simms.

In 1955 Theorell was awarded the Nobel Prize in Physiology or Medicine "for his discoveries relating to the nature and mode of action of oxidation enzymes." 

In 1968 Khorana shared the Nobel Prize in Physiology or Medicine with R. W. Holley and M. W. Nirenberg "for their interpretation of the genetic code and its function in protein synthesis."

H. G. Khorana, T. M. Jacob, and S. Nishimura were principally responsible for producing evidence confirming the genetic code.  

Sutherland elucidated the role of cyclic adenosine monophosphate, the second messenger mediating actions in a wide range of hormonal effects.

In 1971 Sutherland was awarded the Nobel Prize in in Physiology or Medicine "for his discoveries concerning the mechanisms of the action of hormones."

Ibn-al-Nafis, a Syrian physician, described the lesser circulation in his commentary on the anatomy of the Canon of Avicenna, 1268. This was discovered in three Arabic MSS by Mohyi el Din el Tatawi, who included a German translation in his inaugural dissertation, Der Lungenkreislauf nach el-Koraschi, Freiburg, 1924. According to E. J. Brill's First Encyclopaedia of Islam (1913-1936) p. 95, this dissertation was issued in only 5 manuscript copies. Meyerhof included 29 pages of Arabic text in the above paper, which appears to represent the first appearance of the relevant Arabic text of Ibn-al-Nafis in print. English translations are in Ann. Surg., 1936, 104, 1-8, and in Bull. med. Hist., 1955, 29, 430-40. See John B. West, "Ibn al-Nafis, the pulmonary circulation, and the Islamic Golden Age," J Appl Physiol (1985). 2008 Dec; 105(6): 1877–1880.

Contains (pp. 168-73) the first printed description of the lesser circulation. Because of the heretical nature of this book on the reform of Christianity, it was printed secretly and anonymously at Vienne, France. Copies had circulated in manuscript as early as 1546.

As a punishment for heresy, Servetus, a physician, was burnt at the stake at Champel, Geneva, by order of Calvin, soon after publication. Virtually the entire edition of 1000 copies was burned with him. Only three copies survive: Richard Mead’s copy in the Bibliothèque nationale de France, a copy in the Imperial Library, Vienna, and a copy lacking the title page and the first 16pp., said to be Calvin’s personal copy, at Edinburgh University Library.

Servetus's passage on the lesser circulation was first reprinted by William Wotton in Reflections upon ancient and modern learning (1694), pp. 211-12. Wotton provided the Latin text on pp. 230-31 of the second edition of Reflexions.... (1697), and in an added "Postscript" that prefixed the second edition he provided the first English translation on pp. xxvi-xxxii. Interestingly, Wotton printed Servetus's text from a transcription provided to him by Charles Bernard; neither Wotton nor Bernard were able to view a copy of the actual book from which it had been copied.

Servetus's complete work was reprinted in type facsimile in 1790 at Nuremberg. Servetus’s passages describing the pulmonary circulation are also translated in J. F. Fulton’s Selected readings in the history of physiology, 2nd ed., 1966, pp. 44-45. See Fulton & Stanton, Michael Servetus, humanist and martyr. With a bibliography of his works, New York: Reichner, 1953.

Digital facsimile of the 1694 edition of Wotton from the Internet Archive at this link. Digital facsimile of the 1697 edition of Wotton at this link. Digital facsimile of the 1790 facsimile from Google Books at this link.

Cesalpino preceded Harvey in the discovery of the concept of the circulation, and Harvey must have known of his ideas, but Cesalpino’s idea of the circulation was not supported by convincing experimental work or quantitative evidence.

A greatly expanded second edition. The results of tying a vein and the centripetal flow in veins were first recorded in print by Cesalpino (lib. ii, Qu. xvii, p. 234). See the English translation, with commentary, of the portions of this work relevant to the circulation by Clark, Nimis and Rochefort in J. hist. med. & all. sci., 1978, 33, 185-213.

Fabricius, teacher of Harvey at Padua, discovered the venous valves, and illustrated them in life-size copperplates in this monograph. He failed to recognize their true function, however, considering their function simply to delay blood flow. Fabricius's work must have influenced Harvey to direct his experimental efforts toward an accurate explanation of the function of the venous valves. This line of research eventually led Harvey to develop an accurate knowledge of how the circulation worked. Facsimile edition, with English translation, edited by K. J. Franklin, 1933. Digital facsimile of the 1603 edition from di.mospace.umsystem.edu at this link.

Facsimile reproduction with transliteration of Harvey’s manuscript notes for a Lumleian Lecture, 1616. These show that at that date Harvey had already completed his demonstration of the circulation of the blood. English translation with annotations, Berkeley, 1961. Edited, with an introduction, translation, and notes by G. Whitteridge, Edinburgh, 1964.

Discovery and experimental proof of the circulation of the blood. Together with Vesalius’s Fabrica (1543), Harvey’s De motu cordus shares the honor as the greatest book in the history of medicine. Since antiquity, ideas about the physiology and pathology of most parts of the body had been based to an important degree on assumptions made about the function of the heart and blood vessels. In fundamentally changing the conception of these functions, Harvey pointed the way to reform of all of physiology and medicine.

Why Harvey chose a European publisher for his book has long provoked speculation— the most plausible conjecture is that Harvey wanted his book published on the Continent so that it would more easily gain international distribution and acceptance. His choice of the Frankfurt publisher William Fitzer seems to have arisen from his long acquaintance with Robert Fludd, whose books were then being published by Fitzer.The physical distance between Harvey and his publisher seems to have precluded Harvey from correcting proofs, as he was compelled to issue an errata leaf with no less than 126 corrections. Since very few copies of De motu cordis include this errata leaf, it has been argued that it was probably added after a large portion of the edition had already been sold. Even so, Harvey's errata list must have been compiled with some haste, as the Latin text edited by Akenside for the College of Physicians in 1766 contains 246 emendations. Fitzer had Harvey's book printed on paper of poor quality, which has deteriorated in virtually all surviving copies. The first edition must have been relatively small since only about 68 copies have survived, nearly all in institutions. Reprinted in facsimile in 1928 (Monumenta medica, Vol. 5, Florence). The Latin text, with an English translation by K. J. Franklin, was published in Oxford, 1957, and a translation with introduction and notes was published by G. Whitteridge in 1976 (Oxford, Blackwell). See also No. 6l.l.  Digital facsimile from The Warnock Library at this link.

Discovery of the capillary circulation. Malpighi demonstrated that the pulmonary tissues are vesicular in nature and showed that the trachea ends in bronchial filaments. His De pulmonibus includes his demonstration of the capillary anastomosis between arteries and veins. This book, which is very rare, consists of two letters to Borelli describing observations made through the microscope on the lung of a living frog. In the second letter Malpighi described small channels connecting arteries with veins, the capillaries. This was the first proof that blood circulation occurred within a closed hydraulic system. The second edition was published as an appendix to Thomas Bartholin’s De pulmonum substantia et motu diatribe, 1663. It is republished in his Opera omnia, Lugduni Batavorum, 1687, ii, 331. A facsimile was published in Milan in 1958; English translation by J. Young in Proc. roy. Soc. Med., 1929-30, Sect. Hist. Med., 23, 1-11. See No. 915

Lower was the first to demonstrate the scroll-like structure of the cardiac muscle. He was one of the first to transfuse blood. Chapter III of the above work records how Lower injected dark venous blood into the insufflated lungs; he concluded that its subsequent bright red color was due to its absorption of some of the air passing though the lungs. The British Museum copy of this book bears the signature of Walter Charleton, followed by the date “1668”; it is possible, therefore, that the book actually appeared in that year and not in 1669. Facsimile, with translation, London, 1932.

Borelli originated the neurogenic theory of the heart’s action and first suggested that the circulation resembled a simple hydraulic system. He was the first to insist that the heart beat was a simple muscular contraction. One of the founders of biomechanics, Borelli was a representative of the Iatro-Mathematical School, which treated all physiological happenings as rigid consequences of the laws of physics and mechanics.

Borelli’s experiments included what are probably the first measurements of masticatory force.

English translation by P. Maquet from the 1743 edition as On the movement of animals. Berlin: Springer, 1989. 

Digital facsimile of the 1743 edition from the Internet Archive at this link.

Bellini began to develop his hydraulic iatromechanics in this work, in which he considered the blood as a physical fluid with simple mechanical and mathematicizable properties.  He realized the value of the urine as an aid to diagnosis and insisted on its chemical analysis in pathological conditions.

First description of the coronary valves and the venae thebesii.

Discovery of the vasomotor nerves (see also No. 1313).

Hales initiated a new stage in physiological experimentation with his "statical" methods, which were characterized by precise quantitative measurements, repetition and the used of controls, and were based on the assumption that that the known laws of matter operated in the bodies of plants and animals as well as in non-living materials. In his investigations of plant physiology, described in Vegetable Staticks, Hales studied the movement of water in plants, determining that leaf suction is the main force by which water is raised through a plant, and showing that plants lose water constantly via transpiration through their leaves. He also demonstrated that plants do not have a true circulation, and developed techniques to measure the varying rates of growth in different plant structures.

Vegetable Staticks is the first volume of Hales's Statical Essays, the second volume of which (Haemastaticks) appeared in 1733. Haemastaticks ecords Hales' invention of the manometer, with which he was the first to measure blood-pressure. His work is the greatest single contribution to our knowledge of the vascular system after Harvey, and led to the development of the blood-pressure measuring instruments now in universal use.

In the course of his work Hales indirectly discovered vasodilatation and vasoconstriction. Concluding that the force of the arterial blood in the capillaries could not be sufficient to produce muscular motion, he suggested a force regulated by the nerves, and perhaps electrical. "Hales was therefore the first physiologist to suggest, with some evidence to support it, the role of electricity in neuromuscular phenomena" (Dictionary of Scientific Biography). Digital facsimile from the Biodiversity Heritage Library at this link.

Taube described the carotid body and named it “ganglion minutum”, See J. Pick, J. Hist. Med., 1959, 14, 61-73.

Carson recognized the vital effect on venous return played by the negative pressure in the pleural cavity.

The first work to apply hydrodynamics to the circulation of the blood.

Poiseuille was the first after Stephen Hales to make any important addition to the knowledge of the physiology of circulation. In his graduation thesis, above, he described a “hemodynamometer” invented by himself and which he used to repeat some of Hales’s blood-pressure experiments. With his hemomanometer, a mercury manometer, which was a great improvement on the long tube used by Hales, Poiseuille showed that the blood-pressure rises and falls on expiration and inspiration, and measured the degree of arterial dilatation produced by each heart beat. English translation in Edinb. med. surg. J., 1829, 32, 28-38. See also his paper in J. Physiol. exp. path., 1828, 8, 272-305. Digital facsimile from the Internet Archive at this link.

Poiseuille’s law of the flow of liquids in tubes – fundamental in blood viscosimetry. Abstract; complete monograph in Mém. Acad. roy. Sci. (Paris), 1846, 9, 433-544. First book-form edition, Paris, 1844.

Marshall Hall clearly distinguished arterioles and venules from capillaries, and he described arteriovenous shunts.

Many of the histological discoveries of Henle are described in the above. He classified tissues histologically. In the section on Gefässnerven (pp. 510, 690) Henle demonstrated the presence of smooth muscle in the endothelial coat of small arteries. Digital facsimile from the Hathi Trust at this link.

Ludwig changed Poiseuille’s hemodynamometer into the kymograph by the addition of a float and caused this float to write on a recording cylinder. Abridged English translation in Ruskin (No. 3160.1).

Vierordt invented a sphygmograph which acted on the principle that indirect estimation of blood-pressure could be accomplished by measuring the counter-pressure necessary to obliterate the arterial pulsation. This was the first instrument with which a tracing of the human pulse could be made. The paper is the first record of a study with an instrument of precision of the pulse in health and disease. Vierordt expanded this work into book form: Die Lehre von Arterienpuls, Braunschweig, Vieweg, 1855.

Faivre made the first accurate estimation of the blood-pressure in man, by connecting the artery with a mercury manometer and making direct readings. These investigations were important, since they established normal values. The paper was republished in book form in 1856. English translation of part 2 in Ruskin (No. 3160.1).

Discovery of the vasoconstrictor and vasodilator nerves and description of their function of regulating the blood supply to the different parts of the body.

Vierordt estimated, by means of a “hemotachometer” of his own invention, the rate of the blood flow in various arteries, and also the influence of the blood volume, pulse rate and respiratory rate upon it.

Invention of the modern sphygmograph. Also published in C.R. Acad. Sci. (Paris), 1860, 51, 281-309. Preliminary paper in same journal, 1860, 50, 634-37.

Ludwig’s inaugural address at Leipzig, in which he introduced the idea of keeping alive excised portions of organs by means of artificial circulation, or perfusion. He suggested that the blood-pressure had a stimulating effect on the vagus.

Invention of the Stromuhr, for measurement of the velocity of the blood. Dogiel was a pupil of Ludwig.

Kries attempted to measure blood pressure in the capillaries by using a skin blanching method.

Stricker was the first to describe vasodilatation on stimulation of the posterior nerve roots.

Rouget made an important investigation of the control of capillary circulation. He described cells (“Rouget’s cells”) on the outer surfaces of capillary walls, considered to be contractile. English translation in No. 1588.3.

Like Braune’s other anatomical works, this is notable for its excellent illustrations.

Translated into English as "The contraction of the vena portae and its influence upon the circulation," Johns Hopkins Hospital Reports, I (1896) 111-157. Digital facsimile of the English translation from Google Books at this link.

“Following coronary ligation Porter noted that the procedure frequently resulted in fibrillary contractions of the heart and sudden death. However, death did not always occur and this led him to conclude that Cohnheim’s (1881) consistently fatal results were due to operative trauma and that the coronary arteries were not end arteries” (Willius & Dry).
Digital facsimile from PubMedCentral at this link.

Continued with his "Further researches on the closure of the coronary arteries," J. exp. Med., 1 (1896) 46-70. Digital facsimile from PubMedCentral at this link.

The physiological wave sometimes found in mid-diastole, when the pulse is slow, was first described by Gibson. He termed it the b-wave.
Gibson worked with William Osler at the Radcliffe Infirmary in Oxford, and cared for the Regius Professor during his last illness. Gibson also performed Osler's autopsy.

“Hartmann’s critical point”, the site on the large intestine where the lowest sigmoid artery meets the superior rectal arterial branch.

Lombard soaked the skin in cedarwood oil, rendering transparent the superficial epidermal layers, and thus making possible many direct observations on it.

First description of the carotid sinus depressor reflex.

Dale and Richards studied the effect of histamine on the control of the circulation and showed its peripheral action to be located in the capillaries and smaller arterioles.

Silliman Lectures. Krogh was first to describe the adaptation of blood perfusion in muscle and other organs according to demands through opening and closing the arterioles and capillaries.

In 1920 Krogh received the Nobel Prize in Physiology or Medicine "for the discovery of the mechanism of regulation of the capillaries in skeletal muscle." 

Besides his contributions to medicine, Krogh was one of the founders of the company known today as Novo Nordisk. 

First description of the structure and function of the sinus nerve and the reflex character of carotid pressure.

Direct measurement of the blood pressure within the capillaries.

First practical method of measuring circulation time. 

Digital facsimile of most of the papers in this series are available from PubMedCentral.

Introduction of the Thermostromuhr, an instrument for measuring the velocity of the blood flow.

Wiggers, professor of physiology at the Western Reserve University, Cleveland, contributed much to the knowledge of the circulation and devised several instruments to promote the study of this subject.