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UNDERSTANDING of HORMONE SYSTEMS * Hormones, or "internal secretions" are derived from glands. The organs known to produce hormones are the pituitary, the thyroid, the parathyroid, the adrenals, the pancreas, the stomach, and the intestines(1). In about 30AD, diseases were thought to be caused by the lack of an unknown substance which came from different organs. Therefore, it was assumed, diseases could be treated by artificially adding the appropriate missing substance. The method became known as opotherapy(1). A better insight came at the end of the 16th century, when Paracelsus wrote "heart cures heart, spleen spleen, lungs lungs"(2). To be followed in the 1640`s by Thomas Willis who noted: "blood pours out something - through spermative arteries to the genitals, so also it receives as a recompense a certain ferment from these parts - to wit, certain particles imbuted with a seminal tincture are carried back to the blood... which make it vigorous and inspire into it a new and likely virtue"(3). In 1786 Caleb Parry noted occasional occurrence of exophthyalmic goitre in human patients and recorded the signs of protruding eyeballs, heart palpitations, and a swelling of the thyroid gland. Parry recorded 8 such cases, and identified a connection(4). The first morphological evidence that materials can pass from glands into the blood circulation system came in 1836, when King observed, under a microscope, colloid from the thyroid gland transfer into the lymphatics and then into the general circulation(4). In 1840, Mohr conducted a post-mortem examination of patient who, before death, had shown signs of loss of memory, partial blindness, and imbecility - and found a tumour-like degeneration of the pituitary gland(4). Claude Bernard claimed, in 1848, to have discovered "in fasting animals there is no trace of blood in the portal vein, the sugar appears only in the vein that issues from the liver. Thus the source of the sugar must be the liver"(5). Yet his biographer, Pierre Mauriac, noted "The experiment that Claude Bernard cites as a guarantee is wrong; he considers it fundamental, but instead it has no value. He was misled by the religion of experimentation"(5). In 1849, refs 1. Hoskins,RG. Endocrinology. Kegan, Paul, Trench, Trubner & Co. 1941. 2. Paracelsus. quoted in ibid. 3. Willis,T. quoted in ibid. 4. Hoskins,RG. Endocrinology. Kegan, Paul, Trench, Trubner & Co. 1941. 5. Mauriac,P. Claude Bernard. ed Bernard Grasset. 3rd ed. 1954. 6. Hoskins,RG. Endocrinology. Kegan, Paul, Trench, Trubner & Co. 1941. |
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UNDERSTANDING of EMBRYONIC DEVELOPMENT Presumably, a reference (by supporters of animal experiments) to the supposed discovery of the "organizer effect" in embryonic development by Hans Spemann, who in 1901 cauterized the prospective opening in the retina in the developing stage of Rana fusca tadpole. A few days later, on the side on which he had operated, the eye and lens were missing. Where the retina had not been totally destroyed, the ability to form lenses appeared to correlate with the ability of the remnant to contact the overlying ectoderm. Spemann claimed that contact of the optic vesicle with the overlying ectoderm was needed to turn that ectoderm into a lens, but did not know whether or not it was a sufficient cause; nor did he know if the optic cup instructed the ectoderm to form a lens or acted as a trigger allowing expression of pre-existing potency. He admitted these transplantations were difficult to perform and he was unsuccessful(1). Two years after this, Spemann showed, in constricted eggs, two neural axes form and the extent of the neural tube appeared to correlate with the extent to which the underlying cavity roof of the middle layer of the early embryo had progressed(2). When Ernst Mencl tried repeating Spemann`s experiment, in 1904, he claimed to have got free, unattached, lenses(2). In 1905, Warren Lewis performed the ectopic grafting experiments that Spemann was trying and claimed that the optic cup could cause ectopic lens formation)(2); and Helen King repeated Spemann's ablation experiments on Rana palustris (a related American frog) and got the opposite results: free lenses which were not connected to an eye(3). Spemann proposed a "model" concerning the operculum (in humans, a plug of fibrin and blood cells developing over the site where a developing fertilized foetus has become embedded in the wall of the uterus) of tadpoles(4). He went on to do identical experiment on different species of frog neurulae - "confirming" his earlier results and Helen King's results(5). A component of induction was species-specific, and there seemed to be two ways to make a lens: induction or self-determination. Spemann put his results in the context of his "model". When limbs of amphibian tadpoles arise during metamorphosis, they emerge through an opening called the operculum, through which, it had been thought, the limbs mechanically pushed(6). In 1907, Herman Braus removed the forelimb rudiments - operculum opened at the appropriate time, which he explained by the engineering term "double assurance" - a phrase which entered into embryology(7) but Spemann maintained double assurance also worked for amphibian lenses and that while some frogs had only one mechanism of lens determination, most species were in between and had some self-differentiation but still required contact for optimum lens formation(8). In 1914, Spemann decided to test the state of determination of early salamander gastrula, and transplanted small regions of embryos from one region on one salamander gastrula to a new region on another gastrula. The gastrulae were from differently pigmented specimen of the same species. He then checked whether the transplanted piece differentiated according to its original source or according to its new environment(8). Four years later, he produced a paper, concluding that determination of the neural plate occurs during gastrulation, and the convergent extension of the posterior neural plate. An exception was that the transplanted pieces from early gastrulae were not yet determined. When he had transplanted tissue from the region above the dorsal blastopore lip, the cells formed a second neural tube underlain by a notochord and flanked by two rows of somites(9). Spemann mistakenly believed the upper layer of dorsal blastopore lip gave rise to neural ectoderm (rather than involuting to form chordamesoderm). He thought the dorsal blastopore lip self-differentiated to form neural ectoderm and this initiated a wave of assimilative differentiation spreading anteriorly in the plane of the ectoderm(10). Hans Peter pointed out the errors, and in 1918 Spemann began new heteroplastic transplants where invaginated cells could be more easily identified(11). Three years after Spemann wanted heteroplastic transplants of the dorsal blastopore lip region and gave the task to a graduate student, Hilde Proescholdt(12), while he divided fertilized newt`s eggs into two halves - leaving them connected by a narrow bridge of cytoplasm - with the nucleus in one half and the other only of cytoplasm. Experiments, on pigment and "gray crescent" (the area on one side of the egg, corresponding to the dorsal region of the embryo) in newts` eggs, led Spemann to speculate that if the gray crescent cytoplasm is divided equally between two halves of the egg, two normal embryos develop; if all of the gray crescent cytoplasm is contained in one half of the egg, then a complete embryo is developed only in that half(13). However, the fate of the egg half - whether it develops into a complete embryo or into a "belly" - does not depend upon which half retains the egg nucleus. The half with delayed nuclear supply develops into a complete embryo if it contains the gray crescent cyctoplasm. The half without the gray crescent cytoplasm will become a "belly" even if it contains egg nucleus supply right from the beginning. The difference in the time of nuclear supply and the amount of nuclear material received is completely over-ridden by differences in the cytoplasmic composition of the two egg halves(13). In 1924, Spemann and Proescholdt (now Mangold) published some of their findings on the dorsal blastopore lip transplantations. Dorsal blastopore lip transplants invaginated almost completely, the transplanted tissue caused the formation of a secondary neural plate composed almost entirely of host tissue, and while the notochord was primarily derived from donor tissue, the flanking mesoderm was a combination of donor and host cells. Some somites were chimeric, some completely host, some completely donor. Their paper, with "induction" and "organizer" in its title, was based only on experiments of the 1921-22 breeding seasons(14). Two critical cases where the entire neural plate was composed of host cells were not mentioned in the discussion section of their paper(15). Spemann named the active region, the `organizer` - meaning this was the part which organizes the process of development - the action of which he said "is not a common chemical reaction, but that these processes of development, like all vital processes, are comparable, in the way they are connected, to nothing we know so much as those vital processes of which we have intimate knowledge, viz the physical ones"(16). Subsequent experiments by others failed to bear out Spellman`s opinion, or even supported it in its original form(17). In 1925. Bruno Geinitz, a student of Spemann, found that dorsal blastopore lips transplanted into the blastocoel induced secondary neural tubes(18); and Alfred Marx, another of Spemann`s students, found pure dorsal mesoderm from a late gastrula could induce the neural plate from the ectoderm, while pure ectoderm could not. Spemann now concluded that the dorsal mseoderm was responsible for neural induction(19). Prior to Spemann`s latter experiments, Miller, in 1914, from studies of human ovum, realized the differences between early development of the human embryo and that of other species. In 1927, George Streeter stressed the futility of interpreting the development of humans in terms of the base-line embryology of the frog, the chick, or the rabbit. Streeter provided knowledge of human embryology by his studies of, at the time, the youngest known human embryo(20). refs 1. Spemann,H. Uber Correlationen in der Entwicklung des Auges. Verhand. Anat. Ges. 15: 61-79. 1901. 2. Hamburger,V. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. 3. King,HD. Experimental studies on the eye of the frog embryo. Arch. Ent. Mech. 19: 85-107. 1905. 4. Spemann,H. Zum Problem der Correlation in der tierischen Entwicklung. Verhadl. deutsche zool. Gesell. 17: 22-49. 1907. 5. Spemann,H. Neue Tatsachen zum Linsenproblemen. Zool. Anz. 31. 1907. 6. Spemann,H. Zum Problem der Correlation in der tierischen Entwicklung. Verhadl. deutsche zool. Gesell. 17: 22-49. 1907. 7. Hamburger, V. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. 8. Spemann,H. Zum Problem der Correlation in der tierischen Entwicklung. Verhadl. deutsche zool. Gesell. 17: 22-49. 1907. 9. Spemann,H. Uber die Determination der ersten Organanlagen des Amphibien-embryonen. Zool. Jahr. Supp. 15: 1-48. 1918. 10. Hamburger, V. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. 11. Spemann,H. Entwicklungsphysiologische Studien am Tritonei III. Roux Arch.f. Entw. Mech. 16: 551-631. 1903. 12. Spemann,H. Uber den Anteil von Implantat und Wirtskeim an der Orientierung und Beschaffenheit der Induz Embryonalanlage. Arch. Entw. mech.Org. 123. 1921. 13. Balisnky,BI. Introduction to Embryology. WB Saunders. 1960. 14. Spemann,H. and Mangold,H. Uber Induktion von Embryonanlagen durch Implantation artfremder Organisatoren. Roux' Arch. f. Entw. mech. 100: 1924. 15. Hamburger, V. The Heritage of Experimental Embryology: Hans Spemann and the Organizer. 16. Spemann,H. 1938. quoted in: Balisnky,BI. Introduction to Embryology. WB Saunders. 1960. 17. Balisnky,BI. Introduction to Embryology. WB Saunders. 1960. 18. Geinitz,B. Embryonale Transplantation zwischen Urodelen und Anuren. Roux' Arch. f. Entw. mech. 106: 357-408. 1025. 19. Marx,A. Experimentelle Untersuchungen zur Frage der Determination der Medullar- platte. Roux' Arch. f. Entw. mech. 105: 20 - 44. 1925. 20. Garrison,FH. History of Medicine. 4th ed. WB Saunders Co. 1929. |
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UNDERSTANDING of ENERGY METABOLISM Fernand LaGrange published first textbook on exercise physiology in 1889(1) In 1909, Krogh examined capillaries of the muscles in frogs and mammals through a microscope(2) - but later admitted measurements of the distances between the open capillaries of the muscles made in the frog and in his other animal experiments were inaccurate(3). Krogh found that, in his animal experiments, there was a great variation in the number of capillaries which might be open at any given moment(4). Krogh corrected his errors by concentrating on studying humans as the title of his paper indicates "On the rate of diffusion of carbonic oxide in the lungs of [hu]man[s]" - which showed that the pulmonary circulation and the lungs were merely vehicles for the interchange of oxygen and carbon dioxide and that this occurred at the capillary-aveolar level under certain well-defined laws of physics(5). Sir Archibald Hill, in 1921, fixed the two ends of the thigh muscle of a frog so that the connection did not shorten it and measured the thermal change, but the smallness of the changes caused problems(6). He went on to use a thermopile (a type of battery) but as L G Stevenson pointed out, in his book on Nobel Prize Winners for Medicine or Physiology, "these results cannot be accepted at face value but the factors which distort the results can be eliminated by a control experiment"(7) i.e. clinically. Hill conducted some of the first physiological studies on human athletes(8). Albert Szent-Gynorgi isolated an acidic carbohydrate from cabbage, adrenal glands and lemon juice, which in 1928, he named hexuronic acid(9). Following his isolation of the compound, he found that one milligram protected guinea pigs from scurvy(10). Nine years later, he was awarded the Nobel prize for medicine or physiology and in that year he wrote: "What is healthiful health? Is it full health when a dozen guinea pigs thrive in a protected cage? No. Full health is a condition in which the greatest resistance is offered to all deleterious influences and the most efficient fulfillment of all requirements is attained. Further: What is optimal nutrition; what is the necessary vitamin intake? This cannot be measured on a dozen pampered guinea pigs protected in a cage, and in this sense animal experimentation is entirely misleading"(11). In 1930, Bernado Houssay and his colleagues removed the pancreas of dogs to make them "diabetic" and checked for this by then removing the dog`s pituitary body. Results in the dogs showed an apparently normal carbohydrate metabolism - but, as two medical historians noted "Houssay`s dogs showed... really unstable carbohydrate metabolism so that in a condition of fasting the blood sugar is easily tipped in the direction of hypoglycaemic state (deficient of glucose in the bloodstream)"(12). refs 1. histxphy Exercise Physiology website. 2. Krogh,A. The Anatomy & Physiology of capillaries. Yale Uni Press. 1922. 3. Krogh,A. Journal of Physiology. 1919. 4. Stevenson,LG. Nobel Prize Winners in Medicine or Physiology - 1901-1950. Henry Schuman. 1953. 5. Krogh,A. 1910. in Acierno,LJ. The History of Cariology. Parthenon. 1994. 6. Hill,AV. Les Prix Nobel en 1922. in Stevenson,LG. Nobel Prize Winners in Medicine or Physiology 1901-1950. Henry Schuman. 1953. 7. Stevenson,LG. Nobel Prize Winners in Medicine or Physiology 1901-1950. Henry Schuman. 1953. 8. histxphy Exercise Physiology website. 9. Szent-Gyorgi,A. 1963. in Barker, BM. Bender,DA. Vitamins in Medicine. 4th ed. vol 2. Heinemann. 1982. 10. Sneader,W. Drug Discovery. John Wiley & Sons. 1985. 11. Szent-Gyorgi,A. Deutsch Medizinsche Wochenschrift. vol 63. 1937. 12. Singer,C. Underwood,E. A Short History of Medicine. |
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UNDERSTANDING of the MECHANISM of HEARING In the 1940s, Georg von Bekesky observed a travelling wave which moves up the cochlea. When a single pitch or frequency is applied to the staples in the ear, the basilar membrane starts to move first at the base and progressively later further long the cochlear duct. When he first described the traveling wave he realized that the peak of the wave was much too broad to be able to account for the ability of the ear to distinguish pitches that were very close together. Bekesky experimented with the ears of dead animals and thought that further analysis of frequency took place in the brain - but his idea was wrong, because the nerve fibres leaving a healthy cochlea had already "tuned" to a specific frequency. Also the cochlea had to be healthy with intact OHCs for the timing to work(1). Bekesky developed a structural model of the human ear, using elastic bands, and used extremely intense sound to be able to see the movement. Progressing to using human ears, Bekesky saw the movement within the cochlea of the human ear with the sound level well above the natural range of the inner ear(1). 1. Wright,A. How We Hear: Physiology. in Ballantyne,J et al [eds]. Deafness. 5th ed. Whurr Pub. 1993. |
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UNDERSTANDING of BIOCHEMICAL FUNCTION of the LIVER In 1934, Sir Robert Robinson suggested cholesterol might arise by cyclization of the hydrocarbon squalene(1). Konrad Bloch decided, in the 1950s, to try and verify the hypothesis - as he explained in his acceptance speech of the Nobel Prize for Medicine or Physiology in 1964 "I attempted to demonstrate the formation of squalene from labeled acetate in the shark, an animal species, which accumulates this hydrocarbon in unusually large amounts... Experimentation with intact sharks or with lipid-rich shark liver posed, however, considerable technical difficulties and I failed in the desired objective"(2). In 1952, Bloch and R G Langdon studied squalene synthesis in livers of rats, which Bloch claimed was more successful(2) - but experiments with livers of rats had no clinical value:- "It is not possible to extrapolate directly from rat to human studies because of differences in plasma lipoprotein [cholesterol and trigylcerides] metabolism between species"(3); and "Rats have a much higher activity of the liver enzyme 5-desaturase, which is used in the body to change the chemical structure of fats. This enzyme is found in various tissues in the body including platelets, the liver, adrenal glands, kidneys, and fat"(4). refs 1. Robertson,R. J Chem 2. Bloch,K. Nobel Lecture 3. J of Nutrition. vol 121. 1991. 4. Thatcher,W. Good Medicine. Autumn 1993. |
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UNDERSTANDING of the FUNCTIONS of the BRAIN and BRAIN "MAPPING" In 531BC, Alcmeon first reported that the brain was the seat of thought; and Hippocrates, in 4thc BC, also held the view that the brain was the centre(1) but Aristotle, in 360BC, thought the centre of thought lay within the chest(1). In 1675AD, Leeuwenhoek described nerve fibre under his microscope(1). During the 19thC, exploration of cerebral function by experimental lesions in the nervous system of animals was tried - but Prof Davidson noted "attempts to deduce function from observation of lesions was delusory, interpretation was hardly possible until the concept of localisation of function in separate regions of the nervous system became established"(1). Between 1822 and 1824, Flourens, from experiments on pigeons, concluded that destruction of the cerebrum caused loss of voluntary control but maintained the reflexes; and denied any possibility of cortical localisation(2). In 1861, Paul Broca dissected the body of a woman, who before her death had lost the ability to speak, and found a softened portion in the left frontal lobe of the brain - but his finding was rejected by the medical profession(3) - as it was in contrast with the findings of Flouren`s experiments on pigeons! Three years after Broca, Hughlings Jackson studied human patients and, between 1864 and 1870, wrote that the brain contained a motor region which governed the individual muscular movements of a person. In 1874, Robert Bartholomew studied a terminally-ill patient and shortly before the patient`s death, he stimulated the brain with an electric current and noted that when this was applied to different parts it caused physical responses in certain parts of the body(4). Between 1871 and 1881, Fritsch and Hitzig, Goltz, Ferrier, Munk, and a number of other animal experimenters examined and damaged the brains of dogs and monkeys - the results and the experimenters contradicted each other(5). The editor of the Lancet commented in 1883 "It is an interesting and noteworthy fact that pathological observation is doing more to advance our knowledge of cerebral localization than physiological [animal] experiments"(6). In the 1930s, Harvey Cushing gave a mild stimulation, under anaesthesia, to the brain of a human patient, which established the sensory function of a strip of the surface of the brain(7). Cushing had previously experimented on monkeys but his clinical findings had, obviously, to come from the right line of inquiry - the study of humans. Bernard Hollander wrote, in `Medical Press` in 1931, "It was fantastic to expect a solution of the working of the human brain... from the stimulation or destruction of bits of the cerebral tissues of monkeys, dogs or cats"(8). refs 1. Donaldson,IML. Neuroscience. 2002-3. 2. Garrison,FH. History of Medicine. 4th ed. WB Saunders Co. 1929. 3. Thorwald,J. The Triumph of Surgery. Thames & Hudson. 1960. 4. Stevens,LA. Explorers of the Brain. The Scientific Book Club. 1974. 6. Lancet. 7. Beddow-Bayley,M. Clinical Discoveries. NAVS. 1960. 8. Hollander,B. Medical Press. 20 May 1931. 9. Penfield,W. Proc Royal Soc. vol 134. 1946. |
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UNDERSTANDING of the BASIS of MEMORY In the 1950s, surgical removal of part of the temporal lobe - as the last resort for human patients with severe epileptic seizures - resulted in some suffering from amnesia. But when animal experimenters tried to replicate the clinical finding, it proved impossible to reproduce a comparative loss of memory in animals by the surgical removal of the hippocampus(1). It was reported in 1985 that, some years previously, Sir Frederick Bartlett, an English psychologist, had shown, clinically, that a person tends to remember events and items which fitted into an existing system of knowledge(2). In 1987, M Mishkin and T Appenzeller noted: "Many of the studies leading to the current picture were suggested by case histories of patients, who, because of disease, injury, or surgery affecting specific areas of the brain, lost some of their ability to learn or remember"; and made this comment on animal brains: "The macaque brain is about one-fourth the size of the brain of the chimpanzee, the nearest relative to human beings, and the chimpanzee brain, in turn, is only about one-fourth the size of the human brain. With the increase in size has come greater complexity"(3). refs 1. Mishkin,M. Appenzeller,T. Scientific American. vol 256. June 1987. 2. Reader`s Digest Book of Facts. 1985. 3. Mishkin,M. Appenzeller,T. Scientific American. vol 256. June 1987. |
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