Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Highlights in the History of Physiology Larry H. Bernstein, MD, FCAP, Curator Related Articles: Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics Author and Curator: Larry H Bernstein, MD, FCAP http://pharmaceuticalintelligence.com/2014/11/16/milestones-in-the-evolution-of-diagnostics-in-the-us-healthcare-system-1920s-to-pre-genomics/ Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present Author and Curator: Larry H…
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Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Highlights in the History of Physiology

Larry H. Bernstein, MD, FCAP, Curator

Related Articles:

Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/11/16/milestones-in-the-evolution-of-diagnostics-in-the-us-healthcare-system-1920s-to-pre-genomics/

Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/11/21/diagnostics-industry-and-drug-development-in-the-genomics-era-mid-80s-to-present/

The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/09/the-history-of-infectious-diseases-and-epidemiology-in-the-late-19th-and-20th-century/

The History of Hematology and Related Sciences: A Historical Review of Hematological Diagnosis from 1880 -1980

Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/05/the-history-of-hematology-and-related-sciences/

Outline of Medical Discoveries between 1880 and 1980

Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/03/outline-of-medical-discoveries-between-1880-and-1980/

Selected Contributions to Chemistry from 1880 to 1980

Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/03/selected-contributions-to-chemistry-from-1880-to-1980/

The Evolution of Clinical Chemistry in the 20th Century

Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/13/the-evolution-of-clinical-chemistry-in-the-20th-century/

William Harvey can be credited with founding modern physiology, then Claude Bernard, and then the great anatomist John Hunter, all before the twentieth century.

In the 19th century, curiosity, medical necessity, and economic interest stimulated research concerning the physiology of all living organisms. Discoveries of unity of structure and functions common to all living things resulted in the development of the concept of general physiology, in which general principles and concepts applicable to all living things are sought. Since the mid-19th century, therefore, the word physiology has implied the utilization of experimental methods, as well as techniques and concepts of the physical sciences, to investigate causes and mechanisms of the activities of all living things.

One view of the history of physiology is that it was shortened from a macro-

to a microstructural view with the developments of biochemistry and then molecular biology. Though that view is attractive, it is not really compliant with a holistic view

of human and mammalian development. But form and function are the concern of anatomy and physiology, even with the emergence of a subcellular domain.

William Harvey

William Harvey, discoverer of blood circulation and heart function, was born in 1578 in England. He graduated in Padua in 1602, returned to England, and practiced medicine for a long time. Among his patients were two kings of England (James I and Charles I), and Francis Bacon. He published the work “Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (An Anatomical Dissertation Upon the Movement of the Heart and Blood in Animals) in 1682. It is identified as the beginning of modern experimental physiology. Harvey’s study was based only on anatomical experiments; despite increased knowledge in physics and chemistry during the 17th century, physiology remained closely tied to anatomy and medicine.

The seminal work lays a basic foundation accurately explaining the circulation. In 1609 Harvey was appointed to the staff of St. Bartholomew’s Hospital. He was elected a fellow of the Royal College of Physicians in 1607. His ideas about circulation of the blood were first publicly expressed in lectures he gave in 1616. The work of Aristotle was the basis for Galen’s De usu partium (“On the Use of Parts”) and a source for many early misconceptions in physiology. Galen, the leading physician in ancient times, never thought that the blood circulates.

Harvey first formulated an opinion about the blood circulation by making a simple calculation. Harvey first studied the heartbeat, establishing the existence of the pulmonary (heart-lung-heart) circulation process and noting the one-way flow of blood. When he also realized how much blood was pumped by the heart, he realized there must be a constant amount of blood flowing through the arteries and returning through the veins of the heart, a continuing circular flow. He estimated that the amount of blood that is emitted by each heartbeat about 2 ounces. Because the heart beats 72 times per minute, the sum is about 540 pounds per hour of emitted blood into the aorta. After formulating this hypothesis, he performed experiments and conducted thorough investigation to determine the details of the circulation of the blood.

Harvey stated that arteries carry blood away from the heart while veins carry blood back to the heart. Although Harvey could not visualize the capillaries, the smallest blood vessels that connect the arterioles to small veins, he concluded that there must be capillaries. Harvey pointed out that the function of the heart is to pump blood into the arteries. His theory of the circulation was not readily accepted, Harvey’s work got recognition at the end of his life. The discovery of capillaries by Marcello Malpighi in 1661 provided factual evidence to confirm Harvey’s theory of blood circulation.

Harvey was also involved in the field of Embryology, although less important than the investigation in terms of the circulation of the blood, not something that should be underestimated. He was a careful observer, and his book On the Generation of Animals (On-generation animal world), published in 1651 showed the beginning of the actual field of Embryology. Harvey rejected the theory that the overall structure of the animal body are the same as young and adult animals, the only difference being size. He rightly declared that an embryo grows to its final structure step by step.

http://www.discoveriesinmedicine.com/General-Information-and-Biographies/Harvey-William.html

Herman Boerhaave is sometimes referred to as the father of physiology due to his exemplary teaching in Leiden and his textbook Institutiones medicae (1708).

In the United States, the first physiology professorship was founded in 1789 at the College of Philadelphia, and in 1832, Robert Dunglison published the first comprehensive work on the subject, Human Physiology (Encyclopedia of American History, 2007). In 1833, William Beaumont published a classic work on digestive function.

In the 19th century, physiological knowledge began to accumulate at a rapid rate, in particular with the 1838 appearance of the Cell theory of Matthias Schleiden and Theodor Schwann. It radically stated that organisms are made up of units called cells. Claude Bernard’s (1813–1878) further discoveries ultimately led to his concept of milieu interieur (internal environment), which would later be taken up and championed as “homeostasis” by American physiologist Walter Cannon.

Claude Bernard

Claude Bernard’s first important work was on the functions of the exocrine pancreas; this achievement won him the prize for experimental physiology from the French Academy of Sciences. His most famous work was on the glycogenic function of the liver; in the course of his study he was led to the conclusion that the liver is the seat of an internal secretion, by which it prepares sugar from the elements of the blood passing through it.

In 1851, while examining the effects produced in the temperature of various parts of the body by section of the nerve or nerves belonging to them, he noticed that division of the cervical sympathetic nerve gave rise to more active circulation and more forcible pulsation of the arteries in certain parts of the head, and a few months afterwards he observed that electrical excitation of the upper portion of the divided nerve had the contrary effect. In this way he established the existence of vasomotor nerves, both

vasodilator and vasoconstrictor.

Milieu intérieur is the key process with which Bernard is associated. He wrote, “The stability of the internal environment [the milieu intérieur] is the condition for the free and independent life.”

The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence which the organism has of its external environment, derives from the fact that in the living being, the tissues are withdrawn from external influences and are protected by a veritable internal environment. The constancy of the internal environment is the condition for free and independent life: the mechanism that makes it possible is that which assures the maintenance, within the internal environment, of all the conditions necessary for the life of the elements.

The constancy of the environment presupposes a perfection of the organism such that external variations are at every instant compensated and brought into balance. In consequence, the higher animal is in a close relation with its environment so that its equilibrium results from a continuous and delicate compensation established as if the most sensitive of balances.

In his major discourse on the scientific method, An Introduction to the Study of Experimental Medicine (1865), Bernard described what makes a scientific theory good and what makes a scientist important, a true discoverer. Unlike many scientific writers of his time, Bernard wrote about his own experiments and thoughts, and used the first person.

http://en.wikipedia.org/wiki/Claude_Bernard

Physiology as a distinct discipline utilizing chemical, physical, and anatomical methods began to develop in the 19th century. Claude Bernard in France; Johannes Müller, Justus von Liebig, and Carl Ludwig in Germany; and Sir Michael Foster in England may be numbered among the founders of physiology as it now is known. At the beginning of the 19th century, German physiology was under the influence of the romantic school of Naturphilosophie. In France, on the other hand, romantic elements were opposed by rational and skeptical viewpoints. Bernard’s teacher, François Magendie, the pioneer of experimental physiology, was one of the first men to perform experiments on living animals. Both Müller and Bernard, however, recognized that the results of observations and experiments must be incorporated into a body of scientific knowledge, and that the theories of natural philosophers must be tested by experimentation. Many important ideas in physiology were investigated experimentally by Bernard, who also wrote books on the subject. He recognized cells as functional units of life and developed the concept of blood and body fluids as the internal environment (milieu intérieur) in which cells carry out their activities. This concept of physiological regulation of the internal environment occupies an important position in physiology and medicine; Bernard’s work had a profound influence on succeeding generations of physiologists in France, Russia, Italy, England, and the United States.

Müller’s interests were anatomical and zoological, whereas Bernard’s were chemical and medical, but both men sought a broad biological viewpoint in physiology rather than one limited to human functions. Although Müller did not perform many experiments, his textbook Handbuch der Physiologie des Menschen für Vorlesungen and his personal influence determined the course of animal biology in Germany during the 19th century.

It has been said that, if Müller provided the enthusiasm and Bernard the ideas for modern physiology, Carl Ludwig provided the methods. During his medical studies at the University of Marburg in Germany, Ludwig applied new ideas and methods of the physical sciences to physiology. In 1847 he invented the kymograph, a cylindrical drum that still is used to record muscular motion, changes in blood pressure, and other physiological phenomena. He also made significant contributions to the physiology of circulation and urine secretion. His textbook of physiology, published in two volumes in 1852 and 1856, was the first to stress physical instead of anatomical orientation in physiology. In 1869 at Leipzig, Ludwig founded the Physiological Institute (neue physiologische Anstalt), which served as a model for research institutes in medical schools all over the world. The chemical approach to physiological problems, developed first in France by Lavoisier, was expanded in Germany by Justus von Liebig, whose books on Organic Chemistry and its Applications to Agriculture and Physiology (1840) and Animal Chemistry (1842) created new areas of study both in medical physiology and agriculture. German schools devoted to the study of physiological chemistry evolved from Liebig’s laboratory at Giessen.

The British tradition of physiology is distinct from that of the continental schools. In 1869 Sir Michael Foster became Professor of Practical Physiology at University College in London, where he taught the first laboratory course ever offered as a regular part of instruction in medicine. The pattern Foster established still is followed in medical schools in Great Britain and the United States. In 1870 Foster transferred his activities to Trinity College at Cambridge, England, and a postgraduate medical school emerged from his physiology laboratory there. Although Foster did not distinguish himself in research, his laboratory produced many of the leading physiologists of the late 19th century in Great Britain and the United States. In 1877 Foster wrote a major book (Textbook of Physiology), which passed through seven editions and was translated into German, Italian, and Russian. He also published Lectures on the History of Physiology (1901). In 1876, partly in response to increased opposition in England to experimentation with animals, Foster was instrumental in founding the Physiological Society, the first organization of professional physiologists. In 1878, again due largely to Foster’s activities, the Journal of Physiology, which was the first journal devoted exclusively to the publication of research results in physiology, was initiated.

Foster’s teaching methods in physiology and a new evolutionary approach to zoology were transferred to the United States. in 1876 by Henry Newell Martin, a professor of biology at Johns Hopkins University in Baltimore, Md. The American tradition drew also on the continental schools. S. Weir Mitchell, who studied under Claude Bernard, and Henry P. Bowditch, who worked with Carl Ludwig, joined Martin to organize the American Physiological Society in 1887, and in 1898 the society sponsored publication of the American Journal of Physiology. In 1868 Eduard Pflüger, professor at the Institute of Physiology at Bonn, founded the Archiv für die gesammte Physiologie, which became the most important journal of physiology in Germany.

Physiological chemistry followed a course partly independent of physiology. Müller and Liebig provided a stronger relationship between physical and chemical approaches to physiology in Germany than prevailed elsewhere. Felix Hoppe-Seyler, who founded his Zeitschrift für physiologische Chemie in 1877, gave identity to the chemical approach to physiology. The American tradition in physiological chemistry initially followed that in Germany; in England, however, it developed from a Cambridge laboratory founded in 1898 to complement the physical approach started earlier by Foster.

Physiology in the 20th century is a mature science; during a century of growth, physiology became the parent of a number of related disciplines, of which of comparative physiology and ecophysiology, biochemistry, biophysics, and molecular biology are examples. Major figures in these fields include Knut Schmidt-Nielsen and George Bartholomew. Most recently, evolutionary physiology has become a distinct subdiscipline.

Physiology, however, retains an important position among the functional sciences that are closely related to the field of medicine. Although many research areas, especially in mammalian physiology, have been fully exploited from a classical-organ and organ-system point of view, comparative studies in physiology may be expected to continue. The solution of the major unsolved problems of physiology will require technical and expensive research by teams of specialized investigators. Unsolved problems include the unravelling of the ultimate bases of the phenomena of life. Research in physiology also is aimed at the integration of the varied activities of cells, tissues, and organs at the level of the intact organism. Both analytical and integrative approaches uncover new problems that also must be solved. In many instances, the solution is of practical value in medicine or helps to improve the understanding of both human beings and other animals.

Among areas that have shown significant growth in the twentieth century are endocrinology (study of function of hormones) and neurobiology (study of function of nerve cells and the nervous system).

Fye, B. W. 1987. The Development of American Physiology: Scientific Medicine in the Nineteenth Century. Baltimore: Johns Hopkins University Press.

Rothschuh, K. E. 1973. History of Physiology. Huntington, N.Y.: Krieger.

The Nobel Prize in Physiology or Medicine

Year Laureate[A] Country[B] Rationale[C] 1901 Emil Adolf von Behring Germany “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”[10] 1902 Sir Ronald Ross United Kingdom “for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it”[11] 1903 Niels Ryberg Finsen Denmark

(Faroe Islands) “[for] his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science”[12] 1904 Ivan Petrovich Pavlov Russia “in recognition of his work on the physiology of digestion, through which knowledge on vital aspects of the subject has been transformed and enlarged”[13] 1905 Robert Koch Germany “for his investigations and discoveries in relation to tuberculosis“[14] 1906 Camillo Golgi Italy “in recognition of their work on the structure of the nervous system“[15] Santiago Ramón y Cajal Spain 1907 Charles Louis Alphonse Laveran France “in recognition of his work on the role played by protozoa in causing diseases”[16] 1908 Ilya Ilyich Mechnikov Russia “in recognition of their work on immunity“[17] Paul Ehrlich Germany 1909 Emil Theodor Kocher Switzerland “for his work on the physiology, pathology and surgery of the thyroid gland“[18] 1910 Albrecht Kossel Germany “in recognition of the contributions to our knowledge of cell chemistry made through his work on proteins, including the nucleic substances“[19] 1911 Allvar Gullstrand Sweden “for his work on the dioptrics of the eye“[20] 1912 Alexis Carrel France “[for] his work on vascular suture and the transplantation of blood vessels and organs“[21] 1913 Charles Richet France “[for] his work on anaphylaxis“[22] 1914 Robert Bárány Austria “for his work on the physiology and pathology of the vestibular apparatus“[23] 1919 Jules Bordet Belgium “for his discoveries relating to immunity“[24] 1920 Schack August Steenberg Krogh Denmark “for his discovery of the capillary motor regulating mechanism”[25] 1921 Not awarded 1922 Archibald Vivian Hill United Kingdom “for his discovery relating to the production of heat in the muscle“[26] Otto Fritz Meyerhof Germany “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”[26] 1923 Sir Frederick Grant Banting Canada “for the discovery of insulin“[27] John James Rickard Macleod Canada 1924 Willem Einthoven The Netherlands “for the discovery of the mechanism of the electrocardiogram“[28] 1925 Not awarded 1926 Johannes Andreas Grib Fibiger Denmark “for his discovery of the Spiroptera carcinoma“[29] 1927 Julius Wagner-Jauregg Austria “for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica“[30] 1928 Charles Jules Henri Nicolle France “for his work on typhus“[31] 1929 Christiaan Eijkman The Netherlands “for his discovery of the antineuritic vitamin“[32] Sir Frederick Gowland Hopkins United Kingdom “for his discovery of the growth-stimulating vitamins“[32] 1930 Karl Landsteiner Austria “for his discovery of human blood groups“[33] 1931 Otto Heinrich Warburg Germany “for his discovery of the nature and mode of action of the respiratory enzyme“[34] 1932 Sir Charles Scott Sherrington United Kingdom “for their discoveries regarding the functions of neurons“[35] Edgar Douglas Adrian United Kingdom 1933 Thomas Hunt Morgan United States “for his discoveries concerning the role played by the chromosome in heredity“[36] 1934 George Hoyt Whipple United States “for their discoveries concerning liver therapy in cases of anaemia“[37] George Richards Minot United States William Parry Murphy United States 1935 Hans Spemann Germany “for his discovery of the organizer effect in embryonic development“[38] 1936 Sir Henry Hallett Dale United Kingdom “for their discoveries relating to chemical transmission of nerve impulses“[39] Otto Loewi Austria 1937 Albert Szent-Györgyi von Nagyrapolt Hungary “for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid“[40] 1938 Corneille Jean François Heymans Belgium “for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration“[41] 1939 Gerhard Domagk Germany “for the discovery of the antibacterial effects of prontosil“[42] 1943 Carl Peter Henrik Dam Denmark “for his discovery of vitamin K“[43] Edward Adelbert Doisy United States “for his discovery of the chemical nature of vitamin K“[43] 1944 Joseph Erlanger United States “for their discoveries relating to the highly differentiated functions of single nerve fibres“[44] Herbert Spencer Gasser United States 1945 Sir Alexander Fleming United Kingdom “for the discovery of penicillin and its curative effect in various infectious diseases“[45] Sir Ernst Boris Chain United Kingdom Howard Walter Florey Australia 1946 Hermann Joseph Muller United States “for the discovery of the production of mutations by means of X-ray irradiation“[46] 1947 Carl Ferdinand Cori United States “for their discovery of the course of the catalytic conversion of glycogen“[47] Gerty Theresa Cori, née Radnitz United States Bernardo Alberto Houssay Argentina “for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar“[47] 1948 Paul Hermann Müller Switzerland “for his discovery of the high efficiency of DDT as a contact poison against several arthropods“[48] 1949 Walter Rudolf Hess Switzerland “for his discovery of the functional organization of the interbrain as a coordinator of the activities of the internal organs”[49] António Caetano Egas Moniz Portugal “for his discovery of the therapeutic value of leucotomy (lobotomy) in certain psychoses”[49] 1950 Philip Showalter Hench United States “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”[50] Edward Calvin Kendall United States Tadeusz Reichstein Switzerland

Poland Year Laureate[A] Country[B] Rationale[C] 1951 Max Theiler South Africa “for his discoveries concerning yellow fever and how to combat it”[51] 1952 Selman Abraham Waksman United States “for his discovery of streptomycin, the first antibiotic effective against tuberculosis“[52] 1953 Sir Hans Adolf Krebs United Kingdom “for his discovery of the citric acid cycle“[53] Fritz Albert Lipmann United States “for his discovery of co-enzyme A and its importance for intermediary metabolism”[53] 1954 John Franklin Enders United States “for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue”[54] Frederick Chapman Robbins United States Thomas Huckle Weller United States 1955 Axel Hugo Theodor Theorell Sweden “for his discoveries concerning the nature and mode of action of oxidation enzymes”[55] 1956 André Frédéric Cournand United States “for their discoveries concerning heart catheterization and pathological changes in the circulatory system“[56] Werner Forssmann Federal Republic of Germany Dickinson W. Richards United States 1957 Daniel Bovet Italy “for his discoveries relating to synthetic compounds that inhibit the action of certain body substances, and especially their action on the vascular system and the skeletal muscles”[57] 1958 George Wells Beadle United States “for their discovery that genes act by regulating definite chemical events”[58] Edward Lawrie Tatum United States Joshua Lederberg United States “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria“[58] 1959 Arthur Kornberg United States “for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid“[59] Severo Ochoa Spain

United States 1960 Sir Frank Macfarlane Burnet Australia “for discovery of acquired immunological tolerance“[60] Sir Peter Brian Medawar Brazil

United Kingdom 1961 Georg von Békésy United States “for his discoveries of the physical mechanism of stimulation within the cochlea“[61] 1962 Francis Harry Compton Crick United Kingdom “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”[62] James Dewey Watson United States Maurice Hugh Frederick Wilkins New Zealand

United Kingdom 1963 Sir John Carew Eccles Australia “for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane“[63] Sir Alan Lloyd Hodgkin United Kingdom Sir Andrew Fielding Huxley United Kingdom 1964 Konrad Bloch United States “for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism“[64] Feodor Lynen Federal Republic of Germany 1965 François Jacob France “for their discoveries concerning genetic control of enzyme and virus synthesis“[65] André Lwoff France Jacques Monod France 1966 Peyton Rous United States “for his discovery of tumour-inducing viruses“[66] Charles Brenton Huggins United States “for his discoveries concerning hormonal treatment of prostatic cancer“[66] 1967 Ragnar Granit Finland/Sweden “for their discoveries concerning the primary physiological and chemical visual processes in the eye“[67] Haldan Keffer Hartline United States George Wald United States 1968 Robert W. Holley United States “for their interpretation of the genetic code and its function in protein synthesis“[68] Har Gobind Khorana India Marshall W. Nirenberg United States 1969 Max Delbrück United States “for their discoveries concerning the replication mechanism and the genetic structure of viruses“[69] Alfred D. Hershey United States Salvador E. Luria Italy

United States 1970 Julius Axelrod United States “for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation”[70] Ulf von Euler Sweden Sir Bernard Katz United Kingdom 1971 Earl W. Sutherland, Jr. United States “for his discoveries concerning the mechanisms of the action of hormones“[71] 1972 Gerald M. Edelman United States “for their discoveries concerning the chemical structure of antibodies“[72] Rodney R. Porter United Kingdom 1973 Karl von Frisch Federal Republic of Germany “for their discoveries concerning organization and elicitation of individual and social behaviour patterns”[73] Konrad Lorenz Austria Nikolaas Tinbergen United Kingdom 1974 Albert Claude Belgium “for their discoveries concerning the structural and functional organization of the cell“[74] Christian de Duve Belgium George E. Palade Romania 1975 David Baltimore United States “for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”[75] Renato Dulbecco Italy

United States Howard Martin Temin United States 1976 Baruch S. Blumberg United States “for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases“[76] D. Carleton Gajdusek United States 1977 Roger Guillemin United States “for their discoveries concerning the peptide hormone production of the brain“[77] Andrew V. Schally United States Rosalyn Yalow United States “for the development of radioimmunoassays of peptide hormones“[77] 1978 Werner Arber Switzerland “for the discovery of restriction enzymes and their application to problems of molecular genetics“[78] Daniel Nathans United States Hamilton O. Smith United States 1979 Allan M. Cormack South Africa “for the development of computer assisted tomography“[79] Sir Godfrey N. Hounsfield United Kingdom 1980 Baruj Benacerraf Venezuela “for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions“[80] Jean Dausset France George D. Snell United States 1981 Roger W. Sperry United States “for his discoveries concerning the functional specialization of the cerebral hemispheres“[81] David H. Hubel Canada “for their discoveries concerning information processing in the visual system“[81] Torsten N. Wiesel Sweden 1982 Sune K. Bergström Sweden “for their discoveries concerning prostaglandins and related biologically active substances”[82] Bengt I. Samuelsson Sweden Sir John R. Vane United Kingdom 1983 Barbara McClintock United States “for her discovery of mobile genetic elements“[83] 1984 Niels K. Jerne Denmark “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies“[84] Georges J.F. Köhler Federal Republic of Germany César Milstein Argentina

United Kingdom 1985 Michael S. Brown United States “for their discoveries concerning the regulation of cholesterol metabolism“[85] Joseph L. Goldstein United States 1986 Stanley Cohen United States “for their discoveries of growth factors“[86] Rita Levi-Montalcini Italy 1987 Susumu Tonegawa Japan “for his discovery of the genetic principle for generation of antibody diversity”[87] 1988 Sir James W. Black United Kingdom “for their discoveries of important principles for drug treatment“[88] Gertrude B. Elion United States George H. Hitchings United States 1989 J. Michael Bishop United States “for their discovery of the cellular origin of retroviral oncogenes“[89] Harold E. Varmus United States 1990 Joseph E. Murray United States “for their discoveries concerning organ and cell transplantation in the treatment of human disease”[90] E. Donnall Thomas United States 1991 Erwin Neher Federal Republic of Germany “for their discoveries concerning the function of single ion channels in cells”[91] Bert Sakmann Federal Republic of Germany 1992 Edmond H. Fischer Switzerland

United States “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”[92] Edwin G. Krebs United States 1993 Sir Richard J. Roberts United Kingdom “for their discoveries of split genes“[93] Phillip A. Sharp United States 1994 Alfred G. Gilman United States “for their discovery of G-proteins and the role of these proteins in signal transduction in cells”[94] Martin Rodbell United States 1995 Edward B. Lewis United States “for their discoveries concerning the genetic control of early embryonic development“[95] Christiane Nüsslein-Volhard Federal Republic of Germany Eric F. Wieschaus United States 1996 Peter C. Doherty Australia “for their discoveries concerning the specificity of the cell mediated immune defence“[96] Rolf M. Zinkernagel Switzerland 1997 Stanley B. Prusiner United States “for his discovery of Prions – a new biological principle of infection”[97] 1998 Robert F. Furchgott United States “for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system”[98] Louis J. Ignarro United States Ferid Murad United States 1999 Günter Blobel Germany/United States “for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell”[99] 2000 Arvid Carlsson Sweden “for their discoveries concerning signal transduction in the nervous system“[100] Paul Greengard United States Eric R. Kandel United States Year Laureate[A] Country[B] Rationale[C] 2001 Leland H. Hartwell United States “for their discoveries of key regulators of the cell cycle“[101] Sir Tim Hunt United Kingdom Sir Paul M. Nurse United Kingdom 2002 Sydney Brenner South Africa “for their discoveries concerning ‘genetic regulation of organ development and programmed cell death‘”[102] H. Robert Horvitz United States Sir John E. Sulston United Kingdom 2003 Paul Lauterbur United States “for their discoveries concerning magnetic resonance imaging“[103] Sir Peter Mansfield United Kingdom 2004 Richard Axel United States “for their discoveries of odorant receptors and the organization of the olfactory system“[104] Linda B. Buck United States 2005 Barry J. Marshall Australia “for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease“[105] J. Robin Warren Australia 2006 Andrew Z. Fire United States “for their discovery of RNA interference – gene silencing by double-stranded RNA”[106] Craig C. Mello United States 2007 Mario R. Capecchi United States “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.”[107] Sir Martin J. Evans United Kingdom Oliver Smithies United States 2008 Harald zur Hausen Germany “for his discovery of human papilloma viruses causing cervical cancer“[108] Françoise Barré-Sinoussi France “for their discovery of human immunodeficiency virus“[108] Luc Montagnier France 2009 Elizabeth H. Blackburn United States

Australia “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase“[109] Carol W. Greider United States Jack W. Szostak United States 2010 Sir Robert G. Edwards United Kingdom “for the development of in vitro fertilization“[110] 2011 Bruce A. Beutler United States “for their discoveries concerning the activation of innate immunity“[111] Jules A. Hoffmann France Ralph M. Steinman United States

Canada “for his discovery of the dendritic cell and its role in adaptive immunity“[111]

(awarded posthumously)[112][113] 2012 Sir John B. Gurdon United Kingdom “for the discovery that mature cells can be reprogrammed to become pluripotent“[114] Shinya Yamanaka Japan 2013 James E. Rothman United States “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells“[5] Randy W. Schekman United States Thomas C. Südhof United States 2014 John O’Keefe United States

United Kingdom “for their discoveries of cells that constitute a positioning system in the brain” May-Britt Moser Norway Edvard I. Moser Norway

Footnotes:

In chronological order with prizes not given during war years.

There are distinct categories to observe: infectious disease; vitamins; neurophysiology; biochemistry and molecular biology; immunology and pharmacology; cancer; endocrinology.

There were deserving scientists who did not receive the Nobel Prize: Most notable – were…

Rosalind Franklin, Britton Chance, Bernard Horacker, Allan Wilson, perhaps others..

Excerpt from “Sound and Hearing”, Stevens, S. S., & Warshofsky, Fred,eds., Time-Life Books, NY, 1965. p54 “The molder of the modern theory of basilar-membrane “resonance” is Georg von Bekesy. In 1928 Bekesy was a communications engineer in Budapest, studying the mechanical and electrical adaptation of telephone equipment to the demands of the human hearing mechanism. One day, in the course of a casual conversation, an acquantance asked him whether a major improvement would soon be forthcoming in the quality of telephone systems. The idle remark strarted a chain of thought that eventually posed to Bekesy a more fundamental question: “How much better is the quality of the human ear than that of any telephone system?” His search for the answer has added volumes to our present-day knowledge of hearing.”

a sound impulse sends a wave sweeping along the basilar membrane. As the wave moves along the membrane, its amplitude increases until it reaches a maximum, then falls off sharply until the wave dies out. That point at which the wave reaches its greatest amplitude is the point at which the frequency of the sound is detected by the ear. And as Helmholtz had postulated, Bekesy found that the high-frequency tones were perceived near the base of the cochlea and the lower frequencies toward the apex.”

For his studines of the traveling wave, Georg von Bekesy received the Nobel Prize in 1961. His incredible delicate and elegant experiments had traced sound to the very threshold of sensation. …”

http://hyperphysics.phy-astr.gsu.edu/hbase/sound/bekesy.html

In the 1950s, Wald and his colleagues used chemical methods to extract pigments from the retina. Then, using a spectrophotometer, they were able to measure the light absorbance of the pigments. Since the absorbance of light by retina pigments corresponds to thewavelengths that best activate photoreceptor cells, this experiment showed the wavelengths that the eye could best detect. However, since rod cells make up most of the retina, what Wald and his colleagues were specifically measuring was the absorbance of rhodopsin, the main photopigment in rods. Later, with a technique called microspectrophotometry, he was able to measure the absorbance directly from cells, rather than from an extract of the pigments. This allowed Wald to determine the absorbance of pigments in the cone cells (Goldstein, 2001).

Schack August Steenberg Krogh ForMemRS (November 15, 1874 – September 13, 1949) was a Danish professor at the department of zoophysiology at the University of Copenhagen from 1916-1945.[3][4][5] He contributed a number of fundamental discoveries within several fields of physiology, and is famous for developing the Krogh Principle. In 1920 August Krogh was awarded the Nobel Prize in Physiology or Medicine for the discovery of the mechanism of regulation of the capillaries in skeletal muscle. 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.

Although neurobiology (as it is now called) has always been subsumed under physiology, its rapid growth in the twentieth century, along with its institutionalization in separate university departments and separate funding programs, has made it an almost completely autonomous discipline. Neurobiology can be divided into two major areas: neurophysiology, or the study of the process by which nerve cells transmit a message; and neurology, the study of the structure and organization of the nervous system. A general work is The Neurosciences: Paths of Discovery, edited by Frederic G. Worden, Judith P. Swazey, and George Adelman (Cambridge, Mass.: MIT Press, 1975). Two articles in this collection stand out as particularly interesting: Richard Jung’s “Some European Neuroscientists: A Personal Tribute” (pp. 477-511), and Judith P. Swazey and Frederic G. Worden’s “On the Nature of Research in Neuroscience” (pp. 569-587). Swazey and Worden look at the development of twentieth-century neurobiology in terms of Thomas Kuhn’s concept of scientific revolution.

Two major questions confronted neurologists at the end of the nineteenth and beginning of the twentieth centuries: What was the basic anatomical element of the nervous system (individual cells, or a continuous nerve network)? How were parts of the nervous system (e.g., peripheral nerves and spinal cord) integrated to produce an overall functioning system? The first question involved considerable debate in the period of the 1870s through the 1890s, though it was resolved ultimately in favor of the neuron theory (individual nerve cells as the basic structural and functional unit of the nervous system) by the early 1909.

Central to that debate was the work of the Spanish cytologist Santiago Ramón y Cajal (1852-1934), whose autobiography Recollections of My Life, translated by E. Horne Craigie with the assistance of Juan Cano (Philadelphia: American Philosophical Society, 1937), contains considerable information about the debate, the clash of paradigms, and Ramón y Cajal’s exquisite techniques for bringing about the resolution. A more recent and historically oriented account is Susan Billings’s “Concepts of Nerve Fiber Development 1839- 1930,” Journal of the History of Biology, 1971, 4:275-306, which shows how study of the embryological development of the nervous system (which Ramón y Cajal wisely exploited) helped to demonstrate that the nervous system arises from many discrete individual cells.

The structural and functional organization of the nervous system has been an area of great advancement during the twentieth century. Much work on the mode of action of the reflex response (as well as on how reflexes are learned) and on the relation between inhibition and excitation of nerve tracks was done by Russian neurologists in the latter part of the nineteenth and especially the early part of the twentieth century. The chief figures there were Ivan Michailovich Sechenov (1829-1905) and Ivan P. Pavlov (1849-1936). Pavlov’s inerest in digestion led him, under Sechenov’s infuence, to study the now-classic conditioned reflex involved in salivation. Pavlov’s life and work is the subject of one English-language volume: B.P. Babkin’s Pavlov, A Biography (Chicago: Univ. Chicago Press, 1949). This source provides valuable insight into a whole school of neurological work that has had as much influence on psychology as on neurobiology in this century.

While the general features and functions of the reflex were understood by the turn of the century, its manner of organization (especially in terms of connections with the brain) was not. A towering figure in elucidating the relationship between central and peripheral nervous systems, and especially the integrative function of the spinal cord, was the British physiologist Charles Scott Sherrington (1857-1952). Regnar Granit’s biography, Charles Scott Sherrington, An Appraisal (London: Nelson, 1967), and Judith Swayze’s Reflexes and Motor Integration: Sharington’s Concept of Integrative Action (Cambridge, Mass.: Harvard Univ. Press, 1969) are significant sources. Swayze concentrates on a detailed but clear and insightful analysis of Sherrington’s scientific background, his experimental methods, and the development of his hypotheses about integrative action.

Concerning the development of the neurotransmitter hypothesis (conduction across the synapse between adjacent neurons occurs by a chemical process), its antagonists and protagonists, see Michael V. L. Bennett’s “Nicked by Occam’s Razor: Unitarianism in the Investigation of Synaptic Transmission,” Biological Bulletin, Suppl., June 1985, 168:159-167.

http://depts.washington.edu/hssexec/newsletter/1997/allen.html

Sir John Carew Eccles (27 January 1903 – 2 May 1997) was an Australian neurophysiologist who won the 1963 Nobel Prize in Physiology or Medicine for his work on the synapse. He shared the prize with Andrew Huxley and Alan Lloyd Hodgkin. Eccles and colleagues used the stretch reflex as a model. When Eccles passed a current into the sensory neuron in the quadriceps, the motor neuron innervating the quadriceps produced a small excitatory postsynaptic potential (EPSP). When he passed the same current through the hamstring, the opposing muscle to the quadriceps, he saw an inhibitory postsynaptic potential (IPSP) in the quadriceps motor neuron. Although a single EPSP was not enough to fire an action potential in the motor neuron, the sum of several EPSPs from multiple sensory neurons synapsing onto the motor neuron could cause the motor neuron to fire, thus contracting the quadriceps. On the other hand, IPSPs could subtract from this sum of EPSPs, preventing the motor neuron from firing.

However, neuroscience has been repositioned in the 21st century. Arvid Carlsson, 77, of the University of Gothenburg in Sweden, as well as Paul Greengard of Rockefeller University in New York City, and Eric Kandel of New York’s Columbia University, shared the 2000 Nobel Prize in Physiology or Medicine.

Carlsson overturned conventional wisdom in 1950 by proving that dopamine–once thought to be a mere building block in the synthesis of the neurotransmitter norepinephrine–was an important nervous system messenger in its own right. He and others later discovered that Parkinson’s disease, which causes rigidity and tremors, results from a lack of dopamine in the brain.

Greengard, 74, took Carlsson’s insights several steps further in the 1960s by exploring how dopamine, norepinephrine, and serotonin control transmission of nerve signals at the synapse, the junction between communicating nerve cells. Greengard showed that the three neurotransmitters trigger the addition or removal of phosphate groups to proteins involved in nerve signaling, prompting them to interact with other proteins in a cascade of phosphorylation in and around the synapse.

The discovery that protein phosphorylation is key to nerve cell signaling helped inspire the research of Kandel, 70, who found that the ease with which ions such as calcium pass through a cell membrane– depends on whether the proteins forming the membrane’s pore are phosphorylated. Based on these findings, Kandel showed that short-term and long-term memory are related to the strength and duration of nerve impulses, and that new proteins are synthesized to maintain long-term memory.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, shared the 2013 Nobel Prize in Physiology or Medicine with James Rothman, PhD, a former Stanford professor of biochemistry, and Randy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine. They were awarded the prize “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

“Tom Südhof has done brilliant work that lays a molecular basis for neuroscience and brain chemistry,” said Roger Kornberg, PhD, Stanford’s Mrs. George A. Winzer Professor in Medicine. Kornberg was awarded the Nobel Prize in Chemistry in 2006. He is the son of Arthur Kornberg, in whose lab Schekman received his doctorate.

“The brain works by neurons communicating via synapses,” Südhof said in a phone conversation this morning shortly after the announcement. “We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?” In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice’s synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion.

The Nobel Prize in Physiology or Medicine 2014 was divided, one half awarded to John O’Keefe, the other half jointly to May-Britt Moser and Edvard I. Moser “for their discoveries of cells that constitute a positioning system in the brain.”

In 1971, John O’Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O’Keefe concluded that these “place cells” formed a map of the room.

More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/

History of Physiology

Lois N Magner,

Purdue University, West Lafayette, USA

Published online: April 2001

http://dx.doi.org:/10.1038/npg.els.0003083

Major developments in the history of physiology include William Harvey’s demonstration of the circulation of the blood in the seventeenth century and Claude Bernard’s discovery of internal secretions in the nineteenth century.

For a neglected side of the story, see Seymour S. Cohen’s “The Biochemical Origins of Molecular Biology (Introduction),” Trends in Biochemical Sciences, 1984, 9:334-336, which argues that many of the histories of molecular biology have ignored the contributions of biochemistry to molecular genetics in general and to the discovery of DNA in particular.

Rather than covering the vast array of subjects that rightfully fall under the history of physiology (such as plant physiology and pathology, etc.), I focus on three areas that have been major concerns in the twentieth century: general physiology, neurobiology and endocrinology. For a brief introduction and overview of twentieth-century physiology, it is worthwhile to consult Karl E. Rothschuh’s History of Physiology (Huntington, N.Y.: Krieger, 1973). Chapter 7 (pp. 264-361) deals with the twentieth century; while it does not provide in-depth coverage, the broad outline establishes the framework within which more specialized topics can be placed.

The Prussian-born American physiologist Jacques Loeb (1859-1924), a long-time investigator at the Rockefeller Institute and a close professional friend of such figures as T. H. Morgan, Boss Harrison, J. McKeen Cattell, and W.J. V. Osterhout, set the style of experimental and quantitative biology that influenced a whole generation of biologists, especially in the United States. Loeb championed what he called “the mechanistic conception of life”–the title of a major address he gave in 1911 and of a book of essays collected in 1912 (Cambridge, Mass.: Harvard Univ. Press, 1964). The reprint edition benefits from a superb introduction by Donald Fleming. The Mechanistic Conception of Life was a celebration of the mechanistic materialist viewpoint in twentieth-century biology. A new biography of Loeb is Philip J. Pauly’s Controlling Life: Jacques Loeb and the Engineering Ideal in Biology (New York: Oxford Univ. Press, 1987). As the title suggests, Pauly emphasizes that Loeb’s guiding ideal was the scientific control of life.

Opposition to the “mechanistic conception of life” came from a number of sources–principally embryology and areas of general physiology–from the 1920s onward. Prominent among those who advanced a more holistic approach were the physiologist Walter Bradford Cannon (1871-1942) and the physiological chemist Lawrence J. Henderson (1878-1942). Cannon’s work, is summarized in his popular book The Wisdom of the Body (1932; New York: Norton, 1960). Henderson’s work is summarized, along with a number of other chemical topics, in his “The Fitness of the Environment” (1913; Boston: Beacon Press, 1958). The development of the idea of homeostasis is the subject of a superb essay by Donald Fleming, “Walter B. Cannon and homeostasis,” Social Research, 1984, 51:609-640.

Henderson’s work has been the subject of several studies. John Parascandola’s “Organismic and Holistic Concepts in the Thought of L. J. Henderson,” Journal of the Histoty of Biology, 1971, 4:63-113, relates Henderson’s scientific to his philosophical work. Henderson and Cannon were strongly interested in social regulation and equilibrium, as was fitting for products of the “Progressive Era,” and sought in physiological processes analogies for the notion of social and economic balance. A specific discussion of Henderson’s view of the interrelationship between social and physiological equilibrium theory can be found in Cynthia Eagle Russett’s The Concept of Equilibrium in American Social Thought (New Haven, Conn.: Yale Univ. Press, 1968). See also Stephen J. Cross and William R. Albury, “Walter B. Cannon, L.J. Henderson, and the Organic Analogy,” Osiris, 1987, N.S. 3:165-192.

Endocrinology (the study of the nature and effect of hormones, or “chemical messengers,” produced by the endocrine glands) is an area of general physiology that has shown enormous growth in the twentieth century. It has also been the subject of numerous historical studies. Arthur F. Hughes has prepared a brief but useful introduction titled “A History of Endocrinology,” Journal of the History of Medcine and Allied Sciences, 1977, 32(3): 292-313. While it is largely descriptive and chronological, Hughes’s study demonstrates the close link between clinical pathology and the gradual discovery of the role of hormones in maintaining physiological balance.

The history of endocrinology is the subject of a special issue of the Journal of the History of Biology, 1976, 9. A general introduction to the historiography of endocrinology is provided for the volume by Diana Long Hall and Thomas F. Click (pp. 229-233). Hall has explored some social and technical aspects of the history of sex-hormone research in “Biology, Sex Hormones, and Sexism in the 1920s,” Philosophical Forum 1974, 5:81-96. She suggests that sexist biases about the importance of male over female hormones proved to be a barrier to the technical solution of problems associated with extracting, isolating, and characterizing the chemical nature of sex hormones (principally testosterone and estrogen) in the 1920s.

On a somewhat more specific aspect of endocrinology, Michael Bliss’s The Discovery of Insulin (Chicago: Univ. Chicago Press, 1982) provides a close picture of the technical problems that investigators in any field of endocrinology had to surmount in order to identify, isolate, and purify a given hormone. The insulin story also provides a fascinating picture of the role of drug companies in encouraging and financing hormone research in the period (1920s) before government subsidy of basic scientific research.

http://depts.washington.edu/hssexec/newsletter/1997/allen.html

Cardiovascular Physiology

The Frank–Starling law of the heart (also known as Starling’s law or the Frank–Starling mechanism or Maestrini heart’s law) states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume) when all other factors remain constant. It is based on the late19th century studies by Otto Frank, who found using isolated frog hearts that the strength of ventricular contraction was increased when the ventricle was stretched prior to contraction. This observation was extended by the elegant studies of Ernest Starling and colleagues in the early 20th century who found that increasing venous return, and therefore the filling pressure of the ventricle, led to increased stroke volume in dogs.

The increased volume of blood stretches the ventricular wall, causing cardiac muscle to contract more forcefully. The stroke volume – contractile force model of Ernest Starling was also based on the earlier observations of Maestrini in 1914. The hypothesis states that “the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fiber.” This allows the cardiac output to be synchronized with the venous return without depending upon external regulation to make alterations. Initial length of myocardial fibers determines the initial work done during the cardiac cycle.

The stroke volume may also increase as a result of greater contractility of the cardiac muscle during exercise, independent of the end-diastolic volume. The Frank–Starling mechanism appears to make its greatest contribution to increasing stroke volume at lower work rates, and contractility has its greatest influence at higher work rates.

The first formulation of the law was theorized by the Italian physiologist Dario Maestrini, who on December 13, 1914, started the first of 19 experiments that led him to formulate the “legge del cuore”. Starling, the holder of the Physiology chair at London University, traced Maestrini’s work in 1918. While Starling was identified for the proposed award of the Nobel Prize, Maestrini never received his recognition, and today the “law of the heart” is known worldwide as “Starling’s Law,” though, among the Italian doctors, it is known by the nickname “Legge di Maestrini”.

One mechanism to explain how preload influences contractile force is that increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber (see Excitation-Contraction Coupling). The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation

It has traditionally been taught that the Frank-Starling mechanism is due to changes in the number of overlapping actin and myosin units within the sarcomere as in skeletal muscle. According to this view, changes in the force of contraction do not result from a change in inotropy. Because we now know that changes in preload are associated with altered calcium handling and troponin C affinity for calcium, a sharp distinction cannot be made mechanistically between length-dependent (Frank-Starling mechanism) and length-independent changes (inotropic mechanisms) in contractile function.

There is no single Frank-Starling curve on which the ventricle operates. There is actually a family of curves, each of which is defined by the afterload and inotropic state of the heart (Figure 2). For example, increasing afterload or decreasing inotropy shifts the curve down and to the right. Decreasing afterload and increasing inotropy shifts the curve up and to the left. To summarize, changes in venous return cause the ventricle to move along a single Frank-Starling curve that is defined by the existing conditions of afterload and inotropy.

Frank-Starling curves show how changes in ventricular preload lead to changes in stroke volume. This graphical representation, however, does not show how changes in venous return affect end-diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular function in terms of pressure-volume diagrams. When venous return is increased, there is increased filling of the ventricle along its passive pressure curve leading to an increase in end-diastolic volume (Figure 3). If the ventricle now contracts at this increased preload, and the afterload is held constant, the ventricle will empty to the same end-systolic volume, thereby increasing its stroke volume. The increased stroke volume is manifested by an increase in the width of the pressure-volume loop. The normal ventricle, therefore, is capable of increasing its stroke volume to match physiological increases in venous return.

Skeletal Muscle Contraction

Muscle Contraction and Relaxation

Step 1

A nerve impulse travels down and axon and causes the release of acetylcholine.

Step 2

Acetylecholine causes the impulse to spread across the surface of the sarcolemma.

Step 3

The nerve impulse enters the T Tubules and Sarcoplasmic Reticulum, stimulating the release of calcium ions.

Step 4

Calcium ions combine with Troponin, shifting troponin and exposing the myosin binding sites on the actin.

Step 5

ATP breaks down ADP + P. The released energy activates the myosin cross bridges and results in the sliding of thin actin myofilament past the thick myosin myofilaments.

Step 6

The sliding of the myofilaments draws the Z lines towards each other, the sarcomere shortens, the muscle fibers contract and therefore muscle contracts.

Step 7

ACh is inactivated by Acetylcholinesterase, inhibiting the nerve impulse conduction across the sarcolemma.

Step 8

Nerve impulse is inhibited, calcium ions are actively transported back into the Sarcoplasmic Reticulum, using the energy from the earlier ATP breakdown.

Step 9

The low calcium concentration causes the myosin cross bridges to separate from the think actin myofilaments and the actin myofilaments return to their relaxed position.

Step 10

Sarcomeres return to their resting lengths, muscle fibers relax and the muscle relaxes.

Pulmonary Gas Exchange

Inhalation (breathing in) is usually an active movement. The contraction of the diaphragm muscles causes the thoracic cavity to increase in volume, thus decreasing the pressures within the lung (Intrapleural and Alveolar Pressures). This negative pressure within the lungs acts as a Pressure Gradient, thus pulling air into the lungs. As air fills the lungs, the negative alveolar pressure moves back towards atmospheric pressure, and air flow into the lungs slows down. In contrast, expiration (breathing out) is usually a passive process.

Where Pel equals the product of elastance E (inverse of compliance) and volume of the system V, Pre equals the product of flow resistance R and time derivate of volume V (which is equivalent to the flow), Pin equals the product of inertance I and second time derivate of V. R and I are sometimes referred to as Rohrer’s constants.

Pulmonary circulation

pulmonary circulation

positive pressure ventilation

hypoxic vasoconstriction

ventilation (physiology), perfusion, ventilation/perfusion ratio (V/Q), and ventilation/perfusion scan

shunts: right-to-left (tetralogy of fallot), left-to-right (patent ductus arteriosus)

respiratory rate and respirometer

Gas exchange/transport (primarily oxygen and carbon dioxide)

Oxygen-hemoglobin dissociation curve

(Bohr effect, Haldane effect)

The Young–Laplace equation (/ˈjʌŋ ləˈplɑːs/) is a nonlinear partial differential equation that describes the capillary pressure difference sustained across the interface between two static fluids, such as water and air, due to the phenomenon of surface tension or wall tension, although usage on the latter is only applicable if assuming that the wall is very thin. The Young–Laplace equation relates the pressure difference to the shape of the surface or wall and it is fundamentally important in the study of static capillary surfaces. It is a statement of normal stress balance for static fluids meeting at an interface, where the interface is treated as a surface (zero thickness).

The equation is named after Thomas Young, who developed the qualitative theory of surface tension in 1805, and Pierre-Simon Laplace who completed the mathematical description in the following year. It is sometimes also called the Young–Laplace–Gauss equation, as Gauss unified the work of Young and Laplace in 1830, deriving both the differential equation and boundary conditions using Johann Bernoulli‘s virtual work principles.

Dalton’s law (also called Dalton’s law of partial pressures) states that in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases. This empirical law was observed by John Dalton in 1801 and is related to the ideal gas laws. Dalton’s law is not strictly followed by real gases with deviations being considerably large at high pressures.

http://en.wikipedia.org/wiki/

Histidine residues in hemoglobin can accept protons and act as buffers. Deoxygenated hemoglobin is a better proton acceptor than the oxygenated form.

In red blood cells, the enzyme carbonic anhydrase catalyzes the conversion of dissolved carbon dioxide to carbonic acid, which rapidly dissociates to bicarbonate and a free proton:

CO2 + H2O → H2CO3 → H+ + HCO3–

By Le Chatelier’s principle, anything that stabilizes the proton produced will cause the reaction to shift to the right, thus the enhanced affinity of deoxyhemoglobin for protons enhances synthesis of bicarbonate and accordingly increases capacity of deoxygenated blood for carbon dioxide. The majority of carbon dioxide in the blood is in the form of bicarbonate. Only a very small amount is actually dissolved as carbon dioxide, and the remaining amount of carbon dioxide is bound to hemoglobin.

In addition to enhancing removal of carbon dioxide from oxygen-consuming tissues, the Haldane effect promotes dissociation of carbon dioxide from hemoglobin in the presence of oxygen. In the oxygen-rich capillaries of the lung, this property causes the displacement of carbon dioxide to plasma as low-oxygen blood enters the alveolus and is vital for alveolar gas exchange.

The general equation for the Haldane Effect is: H+ + HbO2 ←→ H+Hb + O2; however, this equation is confusing as it reflects primarily the Bohr effect. The significance of this equation lies in realizing that oxygenation of Hb promotes dissociation of H+ from Hb, which shifts the bicarbonate buffer equilibrium towards CO2 formation; therefore, CO2 is released from RBCs, so it can diffuse out into the lungs (vs the Bohr effect being most relevant at non high O2 environment tissues; useful comparison to not confuse the 2 concepts of Haldane vs Bohr- Haldane@lung and Bohr@tissues for their physiological relevance).

http://en.wikipedia.org/wiki/Haldane_effect

Liver

In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then, radiographic studies describe an average of twenty segments based on distribution of blood supply. Each segment has its own independent vascular and biliary branches. Surgeons utilize these independent segments when performing liver resection for tumor or transplantation.

There are at least three reasons why segmental resection is superior to simple wedge resection. First, segmental resection minimizes blood loss because vascular density is reduced at the borders between segments. Second, it results in improved tumor removal for those cancers which are disseminated via intrasegmental branches of the portal vein. Third, segmental resection spares normal liver allowing for repeat partial hepatectomy.

Each segment of the liver is further divided into lobules. Lobules are usually represented as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates which radiate from a central vein. Lobules are served by arterial, venous and biliary vessels at their periphery. Human lobules have little connective tissue separating one lobule from another. The paucity of connective tissue makes it more difficult to identify the portal triads and the boundaries of individual lobules. Central veins are easier to identify due to their large lumen and because they lack connective tissue that invests the portal triad vessels.

Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces between the plates of hepatocytes. Sinusoids receive blood from the portal triads. About 25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels. Seventy-five percent of the blood flowing into the liver comes through the portal vein; the remaining 25% is oxygenated blood that is carried by the hepatic artery. The blood mixes, passes through the sinusoids, bathes the hepatocytes and drains into the central vein. About 1.5 liters of blood exit the liver every minute.

The liver is central to a multitude of physiologic functions, including:

Clearance of damaged red blood cells & bacteria by phagocytosis

Nutrient management

Synthesis of plasma proteins such as albumin, globulin, protein C, insulin-like growth factor, clotting factors etc.

Biotransformation of toxins, hormones, and drugs

Vitamin & mineral storage

Kidney

Renal physiology (Latin rēnēs, “kidneys”) is the study of the physiology of the kidney. This encompasses all functions of the kidney, including reabsorption of glucose, amino acids, and other small molecules; regulation of sodium, potassium, and other electrolytes; regulation of fluid balance and blood pressure; maintenance of acid-base balance; the production of various hormones including erythropoietin, and the activation of vitamin D.

Much of renal physiology is studied at the level of the nephron, the smallest functional unit of the kidney. Each nephron begins with a filtration component that filters blood entering the kidney. This filtrate then flows along the length of the nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the blood, and the secretion of wastes from the blood into the urine.

Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is composed of a glomerulus and a Bowman’s capsule. A global assessment of renal function is often ascertained by estimating the rate of filtration, called the glomerular filtration rate (GFR).