CHAPTER 1
1. C.S. Sherrington, The Integrative Action of the Nervous System (New Haven: Yale University Press, 1906), pp. 16–18.
2. There are some excellent works that describe different aspects of this history. See, for example: G. M. Shepherd, Foundations of the Neuron Doctrine (New York: Oxford University Press, 1991); M. Bennett, The History of the Synapse (Australia: Harwood Academic Publishers, 2001); M. W. Cowan and E. Kandell, “A Brief History of Synapses and Synaptic Transmission,” in M. W. Cowan et al., eds., Synapses (Baltimore: Johns Hopkins University Press, 2001), pp. 1–87; J.-C. Dupont, Histoire de la neurotransmission (Paris: Presses universitaires de France, 1991); J. D. Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (1890–1990) (New York: Oxford University Press, 2001).
3. Theodor Schwann’s book was published in German in 1839 and translated into English in 1847. In German, it was entitled Mikroskopische Untersuchungen über die Uebereinstimmung in der Structur und dem Wachstum der Thiere und Pflanzen (Berlin: G. E. Reimer, 1839). See also M. J. Schleiden, “Beiträg zur Phytogenesis,” Archiv für Anatomie, Physiologie und wissenschlaftliche Medicin 5 (1838): 137–176.
4. Experimentation with silver stains was, in part, the result of use of silver in early photography.
5. Wilhelm von Waldeyer introduced the word “neuron” and gave support and name to what became the “neuron doctrine” in his article “Über einige neuer Forschungen im Gebeite der Anatomie des Centralnerven Systems,” Deutsche medizinische Wochenschrift 17 (1891): 1213–1218. Those opposed to the neuron doctrine considered the nervous system to be a “syncytium,” a multinucleated body of protoplasm that is not differentiated into separate cells.
6. Golgi and the members of this side of the dispute were referred to as the reticularists, who argued that the nervous system was a continuous nerve net, or syncitium. The other side argued that neurons were contiguous, but not continuous.
7. S. Ramón y Cajal, Histologie du système nerveux de l’homme et des vertébrés, 2 vols. (Paris: Maloine, 1909–1911).
8. Much of the fundamental observation on the course of nerve degeneration after injury was done earlier by Bernard von Gudden (1824–1886) and later by August-Henri Forel (1848–1931). As was common during their time, both men were psychiatrists as well as neuroanatomists.
9. For more about Golgi, see P. Mazzarello, The Hidden Structure: A Scientific Biography of Camillo Golgi (Oxford: Oxford University Press, 1999), originally published in Italian in 1996; the 1999 edition was edited and translated by Henry A. Buchtel and Aldo Badiani.
10. Golgi presented questionable evidence from studies he had conducted on the cerebellum of the brain, claiming that it showed that there are nerve fibers that are not connected to cell bodies.
11. Hans Held of Leipzig wrote a paper in support of the reticular theory as late as 1929: “Die Lehre von den Neuronen und vom Neurencytium und ihr heutiger Stand,” Fortschritte der Naturwissenschaftlichen Forschung 8 (1929): 117–126.
12. During Cajal’s visit to England in 1894 he was a guest in Sherrington’s home. It has been reported that Sherrington helped prepare many of the slides Cajal used in his Croonian Lecture.
13. A more complete discussion of Sherrington’s adoption of the word “synapse” is given in Bennett, History of the Synapse, pp. 22–24.
14. Moreover, Sherrington felt that the word “synapse” lent itself more readily to being expressed as an adjective (e.g., synaptic junction) than did some of the other alternatives under consideration.
15. Curare had originally been brought from South America, where it was used as a poison for hunting animals. Sir Walter Raleigh and other early explorers were interested in the drug, and by the latter part of the sixteenth century native preparations of the drug had been brought to Europe.
16. A good description of Claude Bernard’s studies of curare is given in Bennett, History of the Synapse, pp. 44–45.
17. E. Du Bois–Reymond, Gesammelte Abhandlungen zur allgemeinen Muskel- und Nervenphysik, vol. 2 (Leipzig: Veit, 1877), p. 700.
18. Du Bois–Reymond succeeded Johannes Müller as head of physiology at the University of Berlin.
19. See M. Grundfest, “Excitation at Synapses,” Journal of Neurophysiology 20 (1957): 316–324. When Du Bois–Reymond compared the effectiveness of electric current with mechanical, thermal, and chemical stimuli (including strychnine) in exciting nerves, he concluded that electric current ranks first, “judging from its convenience, strength, and duration” (quoted in E. Clarke and C. D. O’Malley, The Human Brain and Spinal Cord: A Historical Study Illustrated bv Writings from Antiquity to the Twentieth Century [Berkeley: University of California Press, 1968], p. 199). In 1860 Du Bois–Reymond wrote (Untersuchungen über thierische Elektricität [Berlin: Reiner]) that skeletal muscles were normally alkaline, not acid as commonly thought, but became acid after repeated contractions. The concluding point was that the “physiological reaction of muscle is accompanied by chemical changes.” This is not the same as proposing that neural transmission across a synapse is chemical.
20. Striated muscles have visible striations in the tissue. A major exception to the characterization of visceral organ tissue as smooth is heart muscle, which is striated. Glands are also considered visceral organs, but they have specialized secretory cells that are neither smooth nor striated.
CHAPTER 2
1. J. N. Langley, The Autonomic Nervous System (Cambridge: W. Heffer and Sons, 1921), p. 44.
2. W. Langdon-Brown, The Sympathetic Nervous System in Disease (London: Henry Frowde, 1923), p. 1.
3. E. H. Starling, editor’s preface, in W. H. Gaskell, The Involuntary Nervous System (London: Longmans, Green, 1916).
4. “John Newport Langley, 1852–1925,” Proceedings of the Royal Society of London, series B, part 1 (1925): xxxiii.
5. J. N. Langley, “Walter Holbrook Gaskell, 1847–1914,” The Smithsonian Institution, Annual Report (1915): 531.
6. W. H. Gaskell, The Origin of Vertebrates (London: Longmans, Green, 1908).
7. The term “sympathetic” had earlier been used to refer to what is now known as the entire autonomic nervous system. The word “sympathetic” is derived from the Latin word for “consensus.” In its earlier usage the term referenced the belief that there was a certain interrelationship among the parts of the system that made them respond to each other—this is not unlike the present-day use of the expression “sympathetic vibrations.” Gaskell and Langley used the term “sympathetic” to name the part of the autonomic nervous system that had its origin in the thoracic and lumbar region of the spinal cord. See the chapter “The Vegetative Nervous System” in E. Clarke and L. S. Jacyna, Nineteenth-Century Origins of Neuroscientific Concepts (Berkeley: University of California Press, 1987).
8. Gaskell, Involuntary Nervous System.
9. J. N. Langley, “On the Union of the Cranial Autonomic (Visceral) Fibres with the Nerve Cells of the Superior Cervical Ganglion,” Journal of Physiology, London 23 (1898): 240–270 (quote from p. 251).
10. J. N. Langley and W. L. Dickinson, “On the Local Paralysis of Peripheral Ganglia and the Connection of Different Classes of Nerve Fibers with Them,” Proceedings of the Royal Society of London, series B, 46 (1889): 423–431.
11. Nicotine was isolated from tobacco leaves. Muscarine, which is obtained from the toadstool Amanita muscaria, was found to have many of the same effects on visceral organs as stimulating the parasympathetic system. Pilocarpine, whose action is similar to muscarine, was obtained from the leaflets of a shrub of the genus Pilocarpus. Atropine was obtained from the shrub deadly nightshade, Atropa belladonna. Curare was obtained from South American Indians who used it on their arrows when hunting. The recipe for making curare must have differed somewhat among different tribes, and early on curare was identified by the source or by the container in which it was packaged, such as tubo-curare. The preparation of curare was a carefully kept secret known only to a few shamans of the tribe.
12. Oliver and Schäfer had been students together working under Professor William Sharpley. See E. P. Sparrow and S. Finger, “Edward Albert Schäfer (Sharpley-Schäfer) and His Contributions to Neuroscience: Commemorating the 150th Anniversary of His Birth,” Journal of the History of the Neurosciences 10 (2001): 41–57.
13. G. Oliver and E. A. Schäfer, “On the Physiological Action of Extract of the Suprarenal Capsule,” Journal of Physiology, London 16 (1894): 1–1V; G. Oliver and E. A. Schäfer, “On the Physiological Action of Extract of the Suprarenal Capsule,” Journal of Physiology, London 18 (1895): 230–276.
14. Oliver and Schäfer obtained adrenal extracts from a variety of animals, but mostly from calves, sheep, and guinea pigs.
15. F. Stolz, “Über Adrenalin und Alkylaminoacetobrenzcatechin,” Bericht deutsche Chemie Ges. 37 (1904): 4149–4154; H. D. Dakin, “The Synthesis of a Substance Allied to Noradrenalin,” Proceedings of the Royal Society of London, series B, 76 (1905): 491–497.
16. For more information on the history of adrenal extracts, see H. Davenport, “Epinephrin(e),” Physiologist 25 (1982): 76–82; H. Davenport, “Early History of the Concept of Chemical Transmission of the Nerve Impulse,” Physiologist 34 (1991): 178–190 (esp. p. 181).
17. M. H. Lewandowsky, “Über die Wirkung des Nebennierenextractes auf die glatten Muskeln im Besonderen des Auges,” Archiv für Physiologie: Abteilung des Archives für Anatomie und Physiologie (1899): 360–366. Because the same response was also obtained after excision of the nerve that innervates the muscles of the eye, Lewandowsky concluded that the adrenal extract acted directly on the smooth muscles of the eye.
18. J. N. Langley, “Observations on the Physiological Action of Extract of Supra Renal Bodies,” Journal of Physiology, London 27 (1901): 237–256.
19. See J. D. Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (1890–1990) (New York: Oxford University Press, 2001), p. 81, note 29.
20. J. N. Langley, “Observations on the Physiological Action of Extracts of the Supra-Renal Bodies,” Journal of Physiology, London 27 (1901): 237–256 (quote from p. 247).
21. Langley acknowledged the overlap between his ideas about receptor substances and Paul Erhlich’s theory that “side chains” of a molecule determined the affinity between a chemical substance and a particular cell.
22. Today, receptors are not thought of as endogenous chemicals, but as macromolecules located either in cells or, more commonly, on their outer membranes. These molecular configurations selectively bind other molecules, called ligands, that reach the cell in the form of neurotransmitters, neuromodulators, hormones, and the like from nerves or from the bloodstream. This binding is known to initiate a cascade of biochemical and biophysical reactions that produces changes in the structure and function of the cell.
23. J. N. Langley, “On Nerve Endings and on Special Excitable Substances in Cells (Croonian Lectures),” Proceedings of the Royal Society of London, series B, 78 (1906): 183.
24. For a discussion of the opposition to the Langley’s concept of a “receptor substance,” see A.-H. Maehle, C.-R. Prüll, and R. F. Halliwell, “The Emergence of the Drug Receptor Theory,” Nature Reviews 1 (2002): 637–641.
25. Alfred Clark used a microinjection technique that allowed him to determine that many drugs were active only if injected onto the cell membrane, not into the cell body. He then determined the minimum effective dose and the dose beyond which further increase did not result in any greater intensity of the response. By calculating the size of different drug molecules and the area of the cell surface, Clark was able to conclude that drugs do not act on the entire cell membrane, but only on a finite number of discrete receptors embedded in the membrane. Thus, he wrote, “measurements of the quantities of drugs that suffice to produce an action on cells, prove that in the case of powerful drugs the amount fixed is only sufficient to cover a small fraction of the cell surface…. The simplest probable conception of drug action is that potent drugs occupy certain specific receptors on the cell surface, and that these specific receptors only comprise a small fraction of the total cell surface” (A. J. Clark, The Mode of Action of Drugs on Cells [Baltimore: Williams and Wilkins, 1933], p. 87).
CHAPTER 3
1. There is some disagreement about whether more credit for these ideas should be given to Thomas Elliott or to his mentor, John Langley. See M. Bennett, History of the Synapse (Australia: Harwood Academic Publishers, 2001), pp. 107–108; H. W. Davenport, “Gastrointestinal Physiology, 1895–1975: Motility,” in S. G. Schultz, J. D. Wood, and B. B. Rauner, eds., Handbook of Physiology, sec. 6, vol. 1, part 1 (Bethesda, Md.: American Physiological Society, 1989), pp. 1–101. In most of the literature, Thomas Elliott is given the credit, but this may be due to the precedent established by the writings of Henry Dale, a close personal friend of his.
2. T. R. Elliott, “On the Action of Adrenalin,” Journal of Physiology, London 31 (1904): xx–xxi (quote from p. xxi); T. R. Elliott, “On the Action of Adrenalin,” Journal of Physiology, London 32 (1905): 401–465.
3. Elliott, “Action of Adrenalin” (1905), p. 460.
4. Elliott, “Action of Adrenalin” (1905), pp. 466–467.
5. H. H. Dale, “Thomas Renton Elliott, 1871–1961,” Biographical Memoirs of Fellows of the Royal Society (1961), p. 58.
6. J. N. Langley, The Autonomic Nervous System (Cambridge: W. Heffer and Sons, 1921).
7. Langley, Autonomic Nervous System, pp. 39 and 45.
8. Elliot completed his medical degree with gold medals in clinical medicine and surgery and a prize for his thesis on the innervation of the bladder.
9. T. R. Elliott, “The Adrenal Glands (Sidney Ringer Memorial Lecture, 1914),” British Medical Journal, June 27, 1914, 1395.
10. T. R. Elliot, “The Innervation of the Adrenal Glands,” Journal of Physiology, London 46 (1913): 285.
11. Elliott, “Adrenal Glands (Lecture),” p. 1395.
12. For example, the pupils still dilated in response to nerve stimulation even more than a week after adrenalectomy.
13. Elliott, “Adrenal Glands (Lecture),” p. 1395. Much later, Jacques de Champlain proved that adrenaline secreted by the adrenal medulla is picked up and stored in sympathetic nerves.
14. Langley, Autonomic Nervous System, p. 43.
15. H. H. Dale, Adventures in Physiology (London: Pergamon, 1953).
16. For further information on Thomas Elliott, see “Obituary: Thomas Renton Elliott,” Lancet, March 11, 1961, 567–568; H. P. Himsworth, “Obituary: Prof. T. R. Elliott,” Nature 190 (May 6, 1961): 486–487; H. H. Dale, “Thomas Renton Elliott, 1877–1961,” Royal Society Obituaries and Memoirs, 1830–1998 7 (1961): 53–74; “Obituary: T. R. Elliott,” British Medical Journal, part 1, March 11, 1961, 752–754.
17. Cited p. 6 of J. A. Gunn, “Obituary: Walter Ernest Dixon, 1871–1931,” Journal of Pharmocology and Experimental Therapeutics 44 (1932): 3–21.
18. Atropine was obtained from the plant Atropa belladonna, the deadly nightshade. The name belladonna was derived from the plant’s ability in a very dilute solution to make women more attractive by dilating their pupils. In larger doses atropine is a poison and was used as such in the Middle Ages.
19. W. E. Dixon, “On the Mode of Action of Drugs,” Medical Magazine 16 (1907): 454–457 (quote from pp. 456–457). According to Walter Cannon, Dixon later said that he had submitted the article to a relatively obscure journal because he feared the criticism of his contemporaries: W. B. Cannon, The Way of an Investigator: A Scientist’s Experiences in Medical Research (New York: Hafner, 1945), 99.
20. Dixon did not mention what animal was used as the donor, but Henry Dale reported after Dixon’s death that it had been a dog (British Medical Journal, May 12, 1934, 835). It is likely that Dixon purposely avoided mentioning his use of a dog so that he wouldn’t arouse the ire of the antivivisectionists, who were quite militant in Great Britain at the time.
21. W. E. Dixon, “Vagus Inhibition,” British Medical Journal, 1906, 1807.
22. H. M. McLennan, Synaptic Transmission, 2d ed. (Philadelphia: W. B. Saunder, 1970), p. 24.
23. Dale published data given to him much earlier by W. E. Dixon. The data only illustrated a single example of inhibition in a frog heart exposed to an extract from a dog’s heart obtained after stimulation of the vagus nerve. Without appropriate controls, it is not possible to evaluate the significance of this record. Dale, Adventures in Physiology, p. 532.
24. Cited in In Memory of Sir Henry Dale, Sir Paul Girolami, Lady Helena Taborikova, and Guiseppi Nitisco, eds. (Accademia Roma di Scienze Mediche e Biologiche).
25. H. H. Dale, “Chemical Transmission of the Effects of Nerve Impulses,” British Medical Journal, May 12, 1934, 835–841 (quote from p. 836).
26. G. Barger and H. H. Dale, “Chemical Structure and Sympathetic Action of Amines,” Journal of Physiology, London 41 (1910): 19–59 (quote from p. 54).
27. Reid Hunt was on leave from a position in pharmacology at Johns Hopkins Medical School. In 1904 he joined the U.S. Public Health Service, and in 1913 Hunt was appointed professor of pharmacology at Harvard University. Choline had been found to be present in pig bile in 1849. In 1899 Reid Hunt began to use the acetic ester of choline, acetylcholine, in experiments, but it was not known to be a natural substance until Dale and Dudley found it in animals in 1929.
28. R. Hunt and R. M. Taveau, “On the Physiological Action of Certain Cholin Derivatives and New Methods for Detecting Cholin,” British Medical Journal, part 2, December 22, 1906, 1788–1791. Although acetylcholine had been synthesized in 1867, little was known about its physiological action prior to Hunt’s work.
CHAPTER 4
1. H. H. Dale, “Pharmacology During the Past Sixty Years,” Annual Review of Pharmacology 3 (1963): 1–8 (quote from p. 1).
2. W. Feldberg, “Henry Hallett Dale, 1875–1968,” Biographical Memoirs of Fellows of the Royal Society 13 (1968): 77–174 (esp. p. 87).
3. Created by Sir William Crookes during the late nineteenth century, this sealed glass tube was originally used to determine how gases would change when exposed to an electrical discharge. Wilhelm Roentgen determined it to be the source of what he called X-rays after he discovered patches of fluorescent light on various objects in the room that had been treated with the salts used on photographic plates. In trying to determine what the X-rays could not penetrate, Roentgen inadvertently discovered that the bones of his hand, which were holding a lead pipe, were displayed on a photographic plate. The story of Roentgen and his discovery is described in M. Friedman and G. W. Friedland, Medicine’s Ten Greatest Discoveries (New Haven: Yale University Press, 1998).
4. Feldberg, “Henry Hallett Dale,” p. 93.
5. Feldberg, “Henry Hallett Dale,” pp. 89–91.
6. A. M. Silverstein, Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession (San Diego: Academic Press, 2002).
7. Ehrlich’s ideas about receptors developed first out of his effort to understand why lead and other toxins had an affinity more for certain structures than others. He later revised his ideas about receptors when he started to do his seminal work in immunology, for which he shared the Nobel Prize in 1908. See M. Bennet, History of the Synapse (Australia: Harwood Academic Publishers, 2001), pp. 53–54 for a discussion of Langley and Ehrlich’s theory of receptors.
8. Quoted in E. Bäumler, Paul Ehrlich: Scientist for Life (New York: Holmes and Meier, 1984), p. 81.
9. H. Thoms, “John Stearns and Pulvis Parturiens,” American Journal of Obstetrics and Gynecology 22 (1931): 418–423. John Stearns, “Account of the Pulvis Parturiens, a Remedy for Quickening Childbirth,” was published in the Medical Repository of New York (1818).
10. H. H. Dale, Adventures in Physiology (London: Pergamon, 1953), p. xi.
11. The substance found to produce uterine contractions was later identified as oxytocin, a hormone now known to be produced in the body. Dale described many of the properties of various ergot extracts in H. H. Dale, “On Some Physiological Actions of Ergot,” Journal of Physiology, London 3 (1906): 163–206.
12. H. H. Dale and P. P. Laidlaw, “Histamine Shock,” Journal of Physiology, London 52 (1919): 355. Convincing proof that histamine was present in the body was not actually provided until 1927, when Dale, with Best, Dudley, and Thorpe, was able to extract it from fresh samples of animal liver and lungs. See “The Nature of the Vaso-Dilator Constituents of Certain Tissue Extracts,” Journal of Physiology, London 62 (1927): 397. In the same year Lewis found that histamine was liberated from injured skin and other tissue. Prior to this time, histamine had been called by its chemical name, but when it was found in animal tissue, the name “histamine,” from the Greek histos, meaning “tissue,” was introduced. Histamine is now known to be released from mast cells in the skin and elsewhere in response to injury and to foreign protein. Histamine is also found in the brain and in peripheral nerve trunks. In addition to anaphylactic shock, histamine is known to cause pain, itching, and headaches, among other symptoms, and also to be involved in allergic reactions. In 1919 Dale gave the Croonian Lecture on the subject. See H. H. Dale, “The Biological Significance of Anaphylaxis (Croonian Lecture),” Proceedings of the Royal Society of London, series B, 91 (1919–1920): 126.
13. Quoted in W. Feldberg, “Henry Hallett Dale, 1875–1968,” British Journal of Pharmacology 35 (1969): 1–9 (quote from p. 8).
14. In 1946 Ulf von Euler of Sweden, who shared the 1970 Nobel Prize with Julius Axelrod and Bernard Katz, extracted norepinephrine from the sympathetic nerves of mammals, thereby proving that it was a natural neurotransmitter.
15. H. H. Dale, “The Beginnings and the Prospects of Neurohumoral Transmission,” Pharmacological Reviews 6 (1954): 7–14 (quote from p. 9).
16. R. Hunt and R. M. Taveau, “On the Physiological Action of Certain Cholin Derivatives and New Methods for Detecting Cholin,” British Medical Journal, part 2, December 22, 1906, 1788–1791.
17. Letter, Dale to Elliott, December 11, 1913, Contemporary Medical Archives Center, Wellcome Institute, GC/42. Quoted in E. M. Tansey, “Chemical Transmission in the Autonomic Nervous System: Sir Henry Dale and Acetylcholine,” Clinical Autonomic Research 1 (1991): 63–72.
18. H. H. Dale, “The Occurrence in Ergot and Action of Acetylcholine,” Journal of Physiology, London 48 (1914): iii–iv.
19. H. H. Dale, “The Action of Certain Esters and Ethers of Choline and Their Relation to Muscarine,” Journal of Pharmacology and Experimental Therapeutics 6 (1914): 147–190 (quote from p. 188).
20. At high doses nicotine paralyzes the nerve, allowing no further responses to be evoked.
21. In general, muscarinic sites are located at the junction of parasympathetic nerves with smooth muscles, while nicotinic sites are found primarily at the autonomic ganglia synapses and at the junction of spinal nerves with skeletal muscles. There are, however, some ganglionic synapses that are muscarinic. It is now known that there are both muscarinic and nicotinic receptors in the brain.
22. G. Barger and H. H. Dale, “Chemical Structure and Sympathomimetic Action of Amines,” Journal of Physiology, London 41 (1910): 19–59 (quote from p. 21).
23. Dale, “Action of Certain Esters,” p. 188.
24. Dale, “Action of Certain Esters,” p. 189.
25. H. H. Dale, “Chemical Transmission of the Effects of Nerve Impulses,” British Medical Journal, May 12, 1934, 835–841 (quote from p. 836).
26. Dale, Adventures in Physiology, p. 98.
27. E. D. Lord Adrian, “Sir Henry Dale’s Contribution to Physiology,” British Medical Journal, June 4, 1955, vol. 1, p. 1356.
28. Feldberg, “Henry Hallett Dale,” p. 118.
29. Kymographic drums were cylinders attached to a motor that moved them at a controlled rate. A paper smoked over a kerosene lamp was wrapped around the cylinder. A stylus attached to an electromagnetic device left a mark on the smoked paper when a response occurred. In order to preserve the record, the smoked paper was carefully removed from the drum, soaked in varnish, and hung to dry.
CHAPTER 5
1. O. Loewi, “An Autobiographical Sketch,” Perspectives in Biology and Medicine 4 (1960): 3–25 (quote from p. 3).
2. O. Loewi, “Introduction,” Pharmacological Reviews 6 (1954): 3–6 (quote from p. 3).
3. Otto Loewi’s early life has been described in F. Lembeck and W. Giere, Otto Loewi: Ein Lebensbild in Dokumenten, Biographische Dokumentation und Bibliographie (Berlin: Springer, 1968).
4. Walther Straub was a professor of pharmacology in Marburg for part of the time that Loewi was there.
5. The point where spinal motor nerves join skeletal (voluntary, or striated) muscles is now called the “motor endplate.”
6. Hans Meyer was considered one of the leading pharmacologists in Europe. In 1910, after he became professor of pharmacology in Vienna, Meyer published his famous textbook Experimental Pharmacology as the Basis of Drug Therapy, a book that divorced pharmacology from materia medica and grouped drugs on the basis of the physiological reactions they induced.
7. Loewi’s colleague, a biochemist named Kutscher, had demonstrated that a pancreas could be digested until no protein was left. Loewi’s speculation that animals might be able to make their required proteins from the degraded by-products was shown to be right.
8. Loewi described how he came to do this experiment in O. Loewi, From the Workshop of Discoveries (Porter Lecture Series 19) (Lawrence: University of Kansas Press, 1953), pp. 28–29.
9. Loewi, “Autobiographical Sketch,” p. 10.
10. H. H. Dale, “Otto Loewi, 1873–1961,” Royal Society Obituaries and Memoirs, 1930–1998 8 (1962): 67–89 (quote from p. 71).
11. H. H. Dale, “The Beginning and the Prospects of Neurohumoral Transmission,” Pharmacological Reviews 6 (1954): 7–14 (quote from p. 9).
12. Fletcher was spending the years 1902–1905 working with Loewi in Marburg on the effect of different diuretics on the kidney.
13. O. Schmiedeberg and R. Koppe, Das Muscarin: Das giftige Alkaloid des Fliegenpilzes (Leipzig: Vogel, 1869), pp. 27–29.
14. Eserine is an alkaloid obtained from the Calabar bean. It had been used in the region along the delta of the Niger in trials by ordeal. It was known as early as 1905 that it increased the responses to parasympathetic stimulation. Reid Hunt showed in 1918 that it increased the effects of acetylcholine. That same year, Fühner found that eserine increased the action of acetylcholine on the leech muscle about a million times, but did not increase the potency of either choline or pilocarpine.
15. Loewi, “Autobiographical Sketch,” p. 17.
16. Dale, “Otto Loewi,” p. 76.
17. Loewi, Workshop of Discoveries, p. 33.
18. Horace Davenport may have been the first to discover the discrepancy in the dates as reported by Loewi. See H. Davenport, “Early History of the Concept of Chemical Transmission of the Nerve Impulse,” Physiologist 34 (1991): 178–190. See also Zénon Bacq’s account in his chapter “Chemical Transmission of Nerve Impulses,” in M. J. Parnham and J. Bruinvels, eds., Psycho- and Neuro-Pharmacology, vol. 1 (New York: Elsevier, 1983), pp. 50–103.
19. Loewi, “Autobiographical Sketch,” p. 17.
20. A description of the experiment was first published in a four-page article: O. Loewi, “Über humorale Übertragbarkeit der Herznervenwirkung, I,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 193 (1921): 239–242.
21. Later Loewi found that if he blocked the effect of the vagus nerve by administering atropine, it was easier to obtain acceleration when he stimulated the vagalsympathetic nerve trunk. It was also easier to produce acceleration in the toad heart than in the frog heart.
22. See, for example, W. A. Bain, “A Method of Demonstrating Humoral Transmission of the Effects of Cardiac Vagus Stimulation in the Frog,” Quarterly Journal of Experimental Physiology and Cognate Medical Sciences 22 (1932): 269–274.
23. During February and early March, the time Loewi did his initial experiment, frogs are just emerging from hibernation. The largest and most active frogs are the first to emerge, and it has been suggested that these were the one’s selected by Loewi. See A. H. Fiedman, “Circumstances Influencing Otto Loewi’s Discovery of Chemical Transmission in the Nervous System,” Pflügers Archiv 325 (1971): 85–86. William Van der Kloot has reported that the hearts of the so-called Hungarian frogs, which are the ones Loewi used, contain a relatively low amount of cholinesterase.
24. Zénon Bacq also has written that the details of Loewi’s first experiment differed from his later description. Bacq, who knew Loewi and examined his first publication closely, concluded that in most instances Loewi used only one heart. See Parnham and Bruinvels, eds., Psycho- and Neuro-Pharmacology, pp. 49–103 (especially p. 54).
25. Loewi, “Autobiographical Sketch,” p. 18.
26. For a good review of some of the inconsistencies in Loewi’s description of his experiment, see Davenport, “Early History,” pp. 178–190.
27. A good description of the flaws in the initial data Loewi obtained is presented in J. Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (1890–1990) (New York: Oxford University Press, 2001), pp. 63–68.
28. In German, the series Loewi published was titled “Über humorale Übertragbarkeit der Herznervenwirkung.”
29. Loewi, “Autobiographical Sketch,” p. 18.
30. Loewi’s remark to William Van der Kloot is reported in G. L. Geison, “Loewi, O.,” in C. C. Gillispie, ed., Dictionary of Scientific Biography, vol. 8 (New York: Scribner, 1980), pp. 451–457.
31. The importance of adding physostigmine is made clear in O. Loewi and E. Navratil, “Über humorale Übertragbarkeit der Herznervenwirkung, XI: Über den Mechanismus der Vaguswirkung von Physostigmin und Ergotamin,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 214 (1926): 689–696.
32. Ulf von Euler described the influence that Otto Loewi had on his career in U. von Euler, “Discoveries of Neurotransmitter Agents and Modulators of Neuronal Function,” in F. G. Worden, J. P. Swazey, and G. Adelman, eds., The Neurosciences: Paths of Discovery I (Boston: Birkhaüser, 1992), pp. 180–187.
33. In 1970 von Euler shared the Nobel Prize with Bernard Katz and Julius Axelrod.
34. R. H. Kahn, “Über humorale Übertragbarkeit der Herznervenwirkung,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 214 (1926): 482–498.
35. Bain, “Method of Demonstrating,” pp. 270–271.
36. Quoted in B. Minz, The Role of Humoral Agents in Nervous Activity (Springfield, Ill.: Charles Thomas, 1955), pp. 53–57. According to Zénon Bacq, before Loewi’s first experiment on vagal slowing, Asher had used a similar technique, but he did not find any indication of a neurohumoral secretion. See Z. Bacq, Chemical Transmission of Nerve Impulses: A Historical Sketch (New York: Pergamon, 1975).
37. Cited in E. Clarke and C. D. O’Malley, The Human Brain and Spinal Cord (Berkeley: University of California Press, 1968), p. 252.
38. See Dale, “Otto Loewi” for a complete list of Loewi’s publications.
39. O. Loewi and E. Navratil, “Über humorale Übertragbarkeit der Herznervenwirkung, VI: Der Angriffspunkt des Atropins,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 206 (1924): 123–134; “Über humorale Übertragbarkeit der Herznervenwirkung, VII,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 206 (1924): 135–140; “Über das Schicksal des Vagusstoffs und des Acetylcholins im Herzen,” Klinische Wochenschrift 5 (1926): 894; “Über den Mechanismus der Vaguswirkung von Physistogmin und Ergotomin,” Klinische Wochenschrift 5 (1926): 894–895.
40. E. Engelhardt and O. Loewi, “Termentative Azetylcholinspaltung im blut und ihre Hemmung durch Physostigmin,” Naunyn-Schmeidebergs Archiv für experimentelle Pathologie und Pharmakologie 150 (1930): 1–13.
41. The active ingredient now known as eserine or physostigmine was originally extracted from the West African Calabar bean. It was also called “ordeal bean” because it was used to test criminals. If a suspected criminal survived swallowing the calabar powder, he was said to have passed the “ordeal” test and proven his innocence. The bean was first brought to England in 1840. Around 1863 two sets of investigators obtained the pure alkaloid active ingredient from the bean; one group named it eserine, and the other called it physostigmine. Eserine/physostigmine is now known to inactivate cholinesterase and to prolong and potentiate the effects of acetylcholine. Physostigmine belongs to a group of compounds known as reversible cholinesterase agents. Slightly before and during World War II, a group of highly toxic anticholinesterase compounds known as organophosphates was developed in Germany by I. G. Farben. These compounds were used as insecticides and for nerve gases such as sarin. Some anticholinesterase compounds are used to treat myasthenia gravis, a neurological disorder involving a muscle weakness due to the lack of responsiveness of the acetylcholine receptors stimulated by spinal motor secretions.
42. Cited in Clarke and O’Malley, Human Brain, p. 253.
43. In 1906 Barger, Carr, and Dale had isolated a pharmacologically active substance they called ergotoxine from the ergot fungus. It later was shown to be made up of three separate alkaloid substances. In 1920 Stoll obtained a purified extract of one of these, which he called ergotamine.
44. In 1922 Loewi had found that an ergot extract blocked the action of Acceleransstoff. This was based on Dale’s earlier report that this extract blocked the action of adrenaline. However, this test was not considered to have ruled out other possibilities. In 1926 Loewi demonstrated that ultraviolet light inactivated Acceleransstoff just as it did adrenaline. Finally, in 1936, Loewi demonstrated that Acceleransstoff displays the green fluorescence characteristic of adrenaline. See O. Loewi, “Über humorale Übertragbarkeit der Herznervenwirkung, XVI: Quantitativ und qualitativ Untersuchungen über den Sympathicusstoff,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 237 (1936): 504–514.
45. O. Loewi, “The Humoral Transmission of Nervous Impulse,” Harvey Lectures (1934), pp. 218–233.
46. Dale, “Beginnings,” p. 11.
47. O. Loewi, “The Ferrier Lecture: On Problems Connected with the Principle of Humoral Transmission of Nervous Impulses,” Proceedings of the Royal Society of London, series B 18 (1935): 299–316.
CHAPTER 6
1. H. H. Dale, Adventures in Physiology (London: Pergamon, 1953), p. xv.
2. C. H. Best, H. H. Dale, H. W. Dudley, and W. Z. Thorpe, “The Nature of the Vasodilator Constituents of Certain Tissue Extract,” Journal of Physiology, London 62 (1927): 397–417.
3. H. H. Dale, “Croonian Lectures to the Royal College of Physicians,” Lancet, 1929, part 1, 1179, 1233, 1285.
4. Dale, Adventures, p. xv.
5. Letter Dale to Richards, March 22, 1929, Archives of the National Institute of Medical Research, file 647; quoted in E. M. Tansey, “Chemical Neurotransmission in the Autonomic Nervous System: Sir Henry Dale and Acetylcholine,” Clinical Autonomic Research 1 (1991): 63–72.
6. H. H. Dale and H. W. Dudley, “The Presence of Histamine and Acetylcholine in the Spleen of the Ox and the Horse,” Journal of Physiology, London 68 (1929): 97–123.
7. S. Finger, Minds Behind the Brain: A History of the Pioneers and Their Discoveries (New York: Oxford University Press, 2000), pp. 272–273.
8. Dale and Dudley, “Presence of Histamine,” p. 122.
9. Cited in O. Loewi, “The Chemical Transmission of Nerve Action,” in Nobel Lectures, Including Presentation Speeches and Laureates’ Biographies—Physiology and Medicine, vol. 2 (Amsterdam: Elsevier, 1960), pp. 416–429.
10. To get this effect, eserine had to be administered and the blood supply to the second side had to be intact: B. P. Babkin, A. Alley, and G. W. Stavraky, “Humoral Transmission of Chorda Tympani Effect,” Transactions of the Royal Society of Canada, sec. V: Biological Sciences 26 (1932): 89–107.
11. This has been called the “Vulpian” response for Alfred Vulpian, who first observed it in 1863.
12. H. H. Dale and J. Gaddum, “Reactions of Denervated Voluntary Muscle, and Their Bearing on the Mode of Action of Parasympathetic and Related Nerves,” Journal of Physiology, London 70 (1930): 109–144.
13. The American neurophysiologist Herbert Gasser, who later shared the 1944 Nobel Prize with his collaborator, Joseph Erlanger, suggested an alternative electrical explanation of Dale and Gaddum’s results.
14. B. Minz, “Pharmakologische Untersuchungen am Blutegelpräparat, zugleich eine Methode zum biologischen Nachweis von Acetylcholin bei Anwesenheit anderer pharmakolisch wirksamer körpereigener Stoffe,” Naunyn-Schmeidebergs Archiv für experimentelle Pathologie und Pharmakologie 168 (1932): 292–304; see also B. Minz, The Role of Humoral Agents in Nervous Activity (Springfield, Ill.: Charles Thomas, 1955), pp. 53–57; W. Feldberg and B. Minz, “Das Auftreten eines acetylcholinartigen Stoffes im Nebenierenvenenblut bei Reizung der Nervi splanchni,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 233 (1933): 657–682.
15. W. Feldberg and O. Krayer, “Nachweis einer bei Vagusreiz freiwerdenden azetylcholinähnlichen Substanz am Warmblüterherzen,” Naunyn-Schmeidebergs Archiv für experimentelle Pathologie und Pharmakologie 172 (1933): 170–193.
16. W. Feldberg, Fifty Years On: Looking Back on Some Developments in Neurohumoral Physiology (Sherrington Lectures 16) (Liverpool: Liverpool University Press, 1982), p. 5.
17. W. Feldberg and E. Schilf, Histamin: Seine Pharmakologie und Bedeutung für die Humoralphysiologie (Berlin: J. Springer, 1930).
18. W. Feldberg, “The Early History of Synaptic and Neuromuscular Transmission by Acetylcholine: Reminiscences of an Eye Witness,” in A. L. Hodgkin et al., eds., The Pursuit of Nature: Informal Essays on the History of Physiology (London: Cambridge University Press, 1977), pp. 65–83 (quote from p. 69).
19. Feldberg, Fifty Years On, p. 6.
20. The Rockefeller Foundation insisted on some reasonable assurance that a more permanent position would be offered after the end of the three-year period.
21. Beginning in 1933 and extending until the end of the war in 1945, the Rockefeller Foundation spent $1.5 million in identifying and assisting a total of 303 scientists and scholars from German and other countries as the war extended. Their nationalities were as follows: 191 German; 36 French; 30 Austrian; 12 Italian; 1 Polish; 6 Hungarian; 5 Czechoslovak; 5 Spanish; 2 Danish; 2 Belgian; 2 Dutch; and 1 Finnish. Of the total, 113 were in the social sciences; 73 in the natural sciences; 59 in the humanities; and 58 in the medical sciences. Seven were already Nobel prize winners, two were significant contributors to the making of the atom bomb, and many became heads of prestigious departments in U.S. universities. Ironically, the brilliant mathematics department at the University of Göttingen had been built up earlier with the aid of Rockefeller Foundation funds. When the faculty was dispersed in the thirties many of them ended up at U.S. universities. It has been said that if Hitler had intended to build up mathematics in the United States, a field that had been neglected here, he could hardly have been more successful than what his ruthlessness accomplished. For additional information see R. B. Fosdick, The Story of the Rockefeller Foundation (New York: Harper, 1952).
22. A copy of this letter was made available by the Rockefeller Foundation Archives.
23. For the first six months Feldberg was in London he was able to get some money out of Germany, but after that all his assets were frozen by the Nazi government.
24. Minz, Role of Humoral Agents. For additional information about Bruno Minz see E. Wolfe, A. C. Barger, and S. Benison, Walter B. Cannon: Science and Society (Cambridge, Mass.: Harvard University Press, 2000), pp. 382–383.
25. Some of this story has been described in J. S. Medawar, D. Pyke, and M. Perutz, Hitler’s Gift: The True Story of the Scientists Expelled by the Nazi Regime (UK: General, 2001).
26. For example, in the period from 1990 to 2000, scientists in the United States received 44 Nobel prizes, while German scientists received only 5.
27. H. H. Dale, W. Feldberg, and M. Vogt, “Release of Acetylcholine at Voluntary Nerve Endings,” Journal of Physiology, London 86 (1936): 353–379.
28. M. Vogt, “The Concentration of Sympathin in Different Parts of the Central Nervous System Under Normal Conditions and After the Administration of Drugs,” Journal of Physiology, London 123 (1954): 451–481.
29. The test was adapted from Fühner (see below), who used the technique as a method for detecting the presence of eserine. Minz and Feldberg had turned the method around and used it to detect the presence of acetylcholine.
30. The leech that was used had originally been brought from Hungary. It was important to use the right leech, as it was found that the Hungarian leech (Hirudo officinalis) muscle is much more sensitive to acetylcholine than the English, German, or Israeli leech. The leech preparation was developed by Bruno Minz, a colleague of Wilhelm Feldberg. Minz published the first paper in 1932 describing how the technique could be used to detect acetylcholine. The next year, Feldberg and Minz described the use of the technique to detect acetylcholine in experiments on the cat. The original idea was based on a observation by Fühner, a German pharmacologist, who had reported in 1918 that the leech muscle’s sensitivity to acetylcholine was increased a millionfold by the addition of eserine. Actually, Fühner had been using acetylcholine to detect eserine and Minz and Feldberg reversed the goal of the preparation.
31. J. C. Szerb, “The Estimation of Acetylcholine, Using Leech Muscle in a Microbath,” Journal of Physiology, London 158 (1961): 8P.
32. Besides Wilhelm Feldberg, Dale’s group included, among others: Harold Dudley, John Gaddum, Marthe Vogt, George L. Brown, A. Vartiaimen, and Z. M. Bacq. Brown, Dudley, Feldberg, Gaddum, and Vogt all were elected later to the Royal Society. Brown and Gaddum were also knighted in recognition of their scientific achievements.
33. W. Feldberg and B. Minz, “Das Auftreten eines acetylcholinartigen Stoffes,” p. 657.
34. In 1936 Feldberg left England. He had been offered Rockefeller Foundation support to work with Charles Kellaway at the Walter Eliza Hall Institute in Melboune. As his Rockefeller Foundation support to work in Dale’s laboratory would soon end, he accepted the opportunity. Kellaway was studying the histamine response to snake venom. This was not a new topic for Feldberg—he had published a book on histamine with E. Schilf in 1930 and had also done some research on snake and bee venom in Berlin.
Feldberg did not remain long in Australia, for in 1938 he received an offer to be a reader in physiology at Cambridge. Feldberg was pleased to have an opportunity to return to England, and he soon gained the reputation of being an excellent teacher. He continued his research on acetylcholine, its biosynthesis, and its distribution in the gut. He also became involved in studying the electric fish Torpedo marmorata. The experiments were conducted at Arcachon in the south of France in collaboration with the neurophysiologist Albert Fessard. (Fessard was a neurophysiologist who had for a number of years been quite outspoken in opposing chemical transmission theories.) The electric organ of the Torpedo can be regarded as a collection of muscle end plates, so they suspected that acetylcholine might be involved in triggering the electric shock. The latency in the response when the innervating nerve was stimulated seemed to support the idea that chemical transmission was involved. Feldberg and Fessard applied cholinesterase to the electric organ, and they could then trigger the electrical discharge by applying acetylcholine to the organ. They had also begun to find evidence of the presence of acetylcholine following stimulation of the innervating nerve using the eserine-leech preparation. With these preliminary results in hand and with the help of Dale, Feldberg was able to obtain a Rockefeller Foundation grant to fly to Paris once a month to continue the research on the Torpedo with Fessard. It was 1939 and he was eager to start, but before he could do so the war broke out and the Germans were overrunning France.
Several years after the war, Feldberg was appointed head of the division of physiology and pharmacology at the National Institute of Medical Research (N.I.M.R.). It was 1949 and the institute was in the process of moving from Hampstead to Mill Hill. The research laboratory that Feldberg headed was the same one that Dale had directed for many years. In Mill Hill, Feldberg extended his work on acetylcholine in the brain. Acetylcholine had already been found in the brain, and Feldberg started to collect information about the responses that could be evoked by infusing acetylcholine and eserine into different brain sites.
35. H. H. Dale and W. Feldberg, “The Chemical Transmitter of Effects of the Gastric Vagus,” Journal of Physiology, London 80 (1934): 16P–17P; H. H. Dale, “Nomenclature of Fibres in the Autonomic System and Their Effects,” Journal of Physiology, London 80 (1934): 10P–11P.
36. H. H. Dale and W. Feldberg, “The Chemical Transmission of Secretory Impulses to the Sweat Glands of the Cat,” Journal of Physiology, London 81 (1934): 40P–41P.
37. Dale, “Nomenclature of Fibres,” p. 11P.
38. W. Feldberg and J. Gaddum, “The Chemical Transmitter at Synapses in a Sympathetic Ganglion,” Journal of Physiology, London 81 (1934): 305–319.
39. A.W. Kibjakow, “Über humorale Übertragung der Erregung von einem Neuron auf das andere,” Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere 232 (1933): 432–443. A diagram of Kibjakow’s technique is reproduced in L. H. Marshall and H. W. Magoun, Discoveries in the Human Brain: Neuroscience Prehistory, Brain Structure, and Function (Totawa, N.J.: Humana Press, 1998), p. 168.
40. Eccles and other neurophysiologists argued, for example, that a careful analysis demonstrated that the short latency response of the heart and especially the skeletal muscles could not be induced chemically. Eccles also reported that even large doses of eserine had no appreciable effect on the fast initial response produced by a single preganglionic volley.
41. H. H. Dale, “The Beginnings and the Prospects of Neurohumoral Transmission,” Pharmacological Reviews 6 (1954): 11.
42. One notable exception to the dissenters in 1933 was the neurophysiologist Adrian, who expressed the thought that it was not unreasonable to expect the same principle of chemical transmission to have evolved at all synapses, although not necessarily the same chemicals.
43. Dale, Feldberg, and Vogt, “Release of Acetylcholine.”
44. G. L. Brown, H. H. Dale, and W. Feldberg, “Chemical Transmission of Excitation from Motor Nerve to Voluntary Muscle,” Journal of Physiology, London 87 (1936): 42P–43P. See also Dale, Feldberg, and Vogt, “Release of Acetylcholine.”
45. O. Loewi, “Salute to Henry Hallett Dale,” British Medical Journal, 1955, 1356.
46. M. B. Walker, “Treatment of Myasthenia Gravis with Physostigmine,” Lancet, 1934, 1200–1201. Better results were later found by treating myasthenia gravis with neostigmine and pyridostigmine rather than physostigmine.
47. The author was provided with copies of the nominations for the 1936 Nobel Prize for Physiology or Medicine from the Nobel Archives.
48. In 1938, the year Otto Loewi was arrested by the Nazis after the Germans had annexed Austria, Ernst von Brücke was dismissed from his professorship at Innsbruck. Although Brücke was Protestant, the Nazis charged that both his mother and wife, despite being Protestants, were of Jewish descent. Brücke was eventually brought to Harvard, but he died suddenly in June 1941.
49. All of the letters nominating Otto Loewi and Henry Dale for the Nobel Prize in 1936 were made available to the author through the kindness of the Nobel Archive Committee.
50. O. Loewi, “Problems Connected with the Principle of Humoral Transmission of Nervous Impulses,” Proceedings of the Royal Society of London, series B, 118 (1935): 300.
CHAPTER 7
1. W. B. Cannon, The Way of an Investigator (New York: Hafner, 1965), pp. 59–60.
2. Z.M. Bacq, “Chemical Transmission of Nerve Impulses,” in M. J. Parnham and J. Bruinvels, eds., Psycho- and Neuro-Pharmacology, vol. 1 (New York: Elsevier, 1983), p. 90.
3. One of those who has written that Cannon should have received the Nobel Prize is neuroscientist Ralph Gerard (R. W. Gerard, “Is the Age of Heroes Ended?,” in C. M. Brooks, K. Koizumi, and J. O. Pinkston, eds., The Life and Contributions of Walter Bradford Cannon, 1871–1945 [Brooklyn: State University of New York Press, 1975], pp. 197–208, esp. p. 199).
4. An excellent resource for information about Walter Cannon’s life and work is the two-part biography: S. Benison, A. C. Barger, and E. L. Wolfe, Walter Cannon: The Life and Times of a Young Scientist (Cambridge, Mass.: Harvard University Press, 1987) and E. L. Wolfe, A. C. Barger, and S. Benison, Walter B. Cannon: Science and Society (Cambridge, Mass.: Harvard University Press, 2000). Also useful are Cannon, Way of an Investigator and Brooks, Koizumi, and Pinkston, Life and Contributions.
5. Cannon was also described as being “better than a good sculptor” and once received a blue ribbon for a sculpture he had made of his daughter’s head.
6. Walter Cannon’s former students could later be found in laboratories in thirteen different countries.
7. Cannon described his ancestry and the personality of his parents in the first chapter of Way of an Investigator.
8. Cited in Benison, Barger, and Wolfe, Life and Times.
9. Cannon’s diary entry, July 27, 1892; cited in Benison, Barger, and Wolfe, Life and Times, pp. 19–20.
10. Cited in Benison, Barger, and Wolfe, Life and Times.
11. Cited in Benison, Barger, and Wolfe, Life and Times, p. 25.
12. H. S. Jennings, Behavior of Lower Organisms (Bloomington: Indiana University Press, 1962).
13. Cited in Benison, Barger, and Wolfe, Life and Times.
14. Cited in Benison, Barger, and Wolfe, Life and Times.
15. For a description of Charles Eliot’s presidency at Harvard, see J. M. Burns, Transforming Leadership: A New Pursuit of Happiness (New York: Atlantic Monthly Press, 2003), pp. 67–71.
16. Bowditch had also studied with Carl Ludwig in Leipzig.
17. A brief description of their observations appeared in the journal Science in 1897. Cannon and Moser were among the first to experiment with using a radio-opaque substance in food in order to follow its movement through the alimentary canal and gastrointestinal tract. Cannon also used barium sulphate. He regretted never reporting the use of the barium sulphate, for it later proved to be superior for use in clinical medicine.
18. W. B. Cannon, “The Movement of the Stomach Studied by Means of the Röntgen Rays,” American Journal of Physiology 1 (1899): 359–382.
19. Cited in Benison, Barger, and Wolfe, Life and Times, p. 59.
20. W. B. Cannon, “The Case Method of Teaching Systematic Medicine,” Boston Medical and Surgical Journal 142 (1900): 31–36.
21. One of Cannon’s projects at the time involved using an experimental technique developed by Jacques Loeb to investigate whether some of the impairment from head trauma was the result of oxygen deprivation caused by increased pressure constricting blood vessels. The work on head trauma, which once again combined basic physiology with a clinical problem, attracted some attention when Cannon presented it at a meeting of the Massachusetts Medical Society.
22. Cornelia Cannon seems to have had much of her mother’s energy, self-reliance, and independent spirit. Cornelia’s mother, for example, gave lectures on anarchism to women’s clubs. Cornelia Cannon was particularly active in the birth control movement. She wrote stories for children and several novels, one of which, Red Rust, was quite popular and a financial success.
23. An account of Cornelia and Walter Cannon’s hazardous climb was published in the National Park magazine in 1955. Cannon described the adventure in the second chapter of his book Way of an Investigator.
24. H. H. Dale, “Walter Bradford Cannon, 1871–1945,” Obituary Notices of Fellows of the Royal Society, 1945–1948, vol. 5, pp. 407–423 (quote from p. 413).
25. The committee assuaged Porter by recommending that he be appointed to a newly created chair of comparative physiology.
26. See James’ letter to Sarah Cleghorn dated 1903 in F. J. D. Scott, ed., William James: Selected Unpublished Correspondence, 1885–1910 (Columbus: Ohio State University Press, 1996), pp. 318–319.
27. Cannon’s interest in the physiology of emotion had been stimulated much earlier by an undergraduate class taught by William James. James had proposed that an emotion is experienced when the brain becomes aware of the unique set of peripheral, visceral, and somatic sensations that identify each emotion. For James, emotions were the perceptions of the bodily changes provoked by different stimuli, and he noted that this was reflected in such expressions as “trembling with rage,” “a sinking feeling in the stomach,” and “hair standing on end.” Because this theory had also been proposed by the Danish neurologist Carl Lange it is often called the “James-Lange theory of emotions.”
Cannon had begun to think that William James was wrong. Several lines of evidence suggested that the brain played the primary role in the experience of emotion and that peripheral responses did not differ sufficiently to distinguish between the different emotional states. In 1913 Cannon gave an invited address at the American Psychological Association’s convention in which he emphasized the primary role of the brain in the experience of emotions, but he avoided criticizing his former teacher’s theory. Encouraged by friends, however, when he wrote up the talk for publication in the American Journal of Psychology he included a critique of James’ theory: “We do not feel sorry because we cry, as James contended, but we cry because, when we are sorry or overjoyed or violently angry or full of tender affection—when any of these diverse emotional states is present—there are nervous discharges by sympathetic channels to various viscera, including the lachrymal glands” (W. B. Cannon, “The Interrelations of Emotions as Suggested by Recent Physiological Researches,” American Journal of Psychology 25 [1914]: 252–282).
Cannon also referred to his study of emotions in sympathectomized cats. These are cats in which the chain of sympathetic ganglia have been removed. This operation blocks most of the visceral changes that occur during emotional states and also prevents the brain from receiving information about the state of the visceral organs. This was a difficult surgical procedure that Cannon had mastered. Cannon concluded that sympathectomized cats gave every indication that they were capable of experiencing normal emotions. Cannon also noted that James’ theory could not explain how paraplegics paralyzed from the neck down, whose brain could not receive any sensations from the body, continued to report experiencing different emotions. One such case had recently been reported by C. L. Dana, a New York neurologist.
Much later, long after James’ death, Cannon wrote a stronger critique of the James-Lange theory: W. B. Cannon, “The James-Lange Theory of Emotions: A Critical Examination and an Alternative Theory,” American Journal of Psychology 39 (1927): 106–124. Cannon’s belief that the brain played the primary role in emotions had evolved into a specific theory following the completion of the doctoral dissertation of his student Philip Bard. In 1924 Cannon and Sidney Britton had confirmed earlier reports that cats without their cerebral cortex, so-called decerebrate cats, showed intense rage, often triggered by innocuous stimuli. The following year Cannon suggested to Bard that he might pursue this observation by trying to determine what areas below the cerebral cortex were responsible for this rage. Bard transected the brains of decerebrate cats at different levels and concluded from the results that a region at the border of the thalamus and posterior hypothalamus was responsible for integrating the rage response. These observations led directly to what came to be called the Cannon-Bard “thalamic theory of emotions.” The “thalamic theory” seemed to be supported by several reports from clinical neurologists that following damage to the thalamus, humans often display inappropriate emotions, sometimes crying or laughing for no apparent reason.
28. One of the publications resulting from Cannon’s collaboration with surgeons who performed partial gastrectomies is W. B. Cannon and F. T. Murphy, “The Movement of Stomach and Intestines in Some Surgical Conditions,” Annals of Surgery 43 (1906): 513–537.
29. Cited in C. K. Drinker, “Obituary: Walter Bradford Cannon, 1871–1945,” Science 102 (1945): 470–472.
30. Reported in D. C. Schechter, “Background of Clinical Cardiac Electrostimulation,” New York State Journal of Medicine 72 (1972): 609–610.
31. Roy Hoskins would later edit the journal Endocrinology for a number of years.
32. Cannon regarded most of his own work on the thyroid gland as fruitless. He later wrote that if all his effort “to obtain control of the workings of the thyroid gland could be added to the end of my years, my span of life would be prolonged, I feel sure, by some years.”
33. After some unsuccessful attempts, Cannon improved his methodology by inserting a lubricated catheter in the dissected femoral vein of cats and easing it back into the heart.
34. W. B. Cannon and D. de la Paz, “The Emotional Stimulation of Adrenal Secretion,” American Journal of Physiology 28 (1911): 64.
35. This technique was developed by Rudolph von Magnus in Utrecht.
36. Although germs of the idea had sprung up earlier, strong interest in psychosomatic medicine is thought to have started only with the publication of Helen Dunbar’s book Emotions and Bodily Changes: A Survey of the Literature on Psychosomatic Interrelationships, 1910–1933 (New York: Columbia University Press, 1935).
37. W. B. Cannon and D. de la Paz, “The Stimulation of Adrenal Secretion,” Journal of the American Medical Association 56 (1911): 742.
38. Cannon had been interested in the thyroid gland because he thought its activity was affected by emotional states and he began to think about possible clinical implications. It had occurred to him that some abnormal thyroid conditions produce symptoms similar to those produced by excessive sympathetic nervous system activity. He had in mind hyperthyroidism, where the symptoms include high heart rate, increased metabolism, and weight loss. Cannon wondered if he might be able to demonstrate a neural influence on the thyroid gland if he stimulated the sympathetic system repeatedly.
To overstimulate the thyroid and adrenal glands, Cannon considered the possibility of connecting the phrenic nerve, which innervates the diaphragm, to nerves connected to these glands. The phrenic nerve is activated during each respiration cycle, and, he reasoned, if he could connect the phrenic nerve to the nerves innervating the thyroid and adrenal medulla, these glands would be stimulated with every breath. As Cannon had no experience suturing nerves, he asked his friend, neurosurgeon Harvey Cushing, for help. During the course of one afternoon, Cushing taught Cannon how to connected the phrenic nerve to the nerves innervating the thyroid gland and the adrenal medulla.
During the month that followed the suturing of the nerves, Cannon wasn’t certain that the connections were functional. One afternoon, the animal caretaker reported that one of the cats was losing weight despite eating ravenously. When he examined this cat and others with similarly sutured nerves he found that they all had lost weight and their heart rates were accelerated. A few days later Cannon noticed that with every breath one of a cat’s eyes became exophthalmic, another condition seen in hyperthyroidism. The basal metabolism of the cats was also raised, and on autopsy he found that the weight of the thyroid was three times normal. Cannon became convinced that he was able to produce the main symptoms of hyperthyroidism by excessive stimulation of the thyroid gland. He wanted to extend the use of the same technique to other endocrine conditions and decided to join the phrenic nerve to the branch of the splanchnic that innervates the pancreas to determine if he could produce diabetes by exhausting the capacity of the Langerhans cells to produce insulin.
At a presentation at the Johns Hopkins Medical Society, Cannon not only reported on his experimental technique for producing thyroid pathology, but he also added that the thyroid gland, like the adrenal gland, may also play a role in meeting emergencies: “It is not unreasonable to suppose that the thyroid gland likewise has an emergency function evoked in critical times, which would serve to increase the speed of metabolism when the rapidity of bodily processes might be of the utmost importance, and, besides that, augmenting the efficiency of the adrenin [adrenaline] which would be secreted simultaneously.”
An abstract of Cannon’s presentation, entitled “Some Recent Investigations on Ductless Glands,” was published in 1916 (Johns Hopkins Hospital Bulletin 27 [1916]: 247–248).
39. Around this time, Robert Lovett, professor of orthopedic surgery at Harvard, talked with Cannon about how to measure muscle strength of polio victims, who often suffered from muscle weakness. Lovett was looking for a way to measure muscle strength in order to evaluate the changes that might occur during different exercise and massage regimens.
40. Cannon’s book was well received, and the revised edition published in 1929 was translated into Russian and Chinese.
41. Cannon had become aware of Elliott’s work on adrenaline and the sympathetic nervous system around 1913, and he cited it in an article published in 1914 (American Journal of Physiology 33 [1914]: 372, n. 1). According to Zénon Bacq, Cannon had forgotten about Elliott’s 1904 paper, but one day in 1930 he arrived in the laboratory happily excited after rediscovering it with its statement about adrenaline being liberated every time a sympathetic impulse arrives at its terminal.
42. Cannon also argued that animals without the adrenal medulla might appear normal under protected laboratory conditions, but would not be able to cope with the stresses of a real-life situation. It is now known that even without the adrenal medulla animals seem to cope adequately under more natural conditions.
43. Cannon regarded the introduction of the use of the denervated heart as the most valuable result of the controversy with the Cleveland group. Cannon pointed out that the denervated heart would beat faster when adrenaline was increased by as little as one part in 1,400,000,000 parts of blood (Cannon, Way of an Investigator, p. 101).
44. A brief note by Cannon and Uridil entitled “Some Novel Effects Produced by Stimulating the Nerves of the Liver” was published in Endocrinology 5 (1921): 729–730. For a more complete account see W. B. Cannon and J. E. Uridil, “Studies on the Conditions of Activity in Endocrine Glands, VIII: Some Effects on the Denervated Heart of Stimulating the Nerves of the Liver,” American Journal of Physiology 58 (1921): 353–364. Cannon became more convinced that the liver was the source of a sympathomimetic substance when he found that while fasted animals did not release any of this substance into the blood, in an animal that had eaten meat, a large increase in heart rate and blood pressure was seen following splanchnic nerve stimulation. See also W. B. Cannon and F. R. Griffith, “Studies on the Conditions of Activity in Endocrine Glands, X: The Cardio-Accelerator Substance Produced by Hepatic Stimulation,” American Journal of Physiology 60 (1922): 544–559.
45. Even as late as 1929 Cannon continued to discuss these experiments as merely a response to Stewart and Rogoff’s criticism, thereby overlooking the evidence pointing to the chemical mediation of sympathetic nerve impulses. See, for example, W. B. Cannon, “The Autonomic Nervous System: An Interpretation,” Lancet 1, 1930, 1109–1115.
46. In some experiments, the adrenal glands were removed shortly before the critical test began.
47. W. B. Cannon and Z. Bacq, “Studies on the Conditions of Activity in Endocrine Glands, XXVI: A Hormone Produced by Sympathetic Action on Smooth Muscle,” American Journal of Physiology 96 (1931): 410–411. See also W. B. Cannon and Z. Bacq, “The Mystery of Emotional Acceleration of the Denervated Heart After Exclusion of Known Humoral Accelerators,” American Journal of Physiology 96 (1931): 403; H. F. Newton, R. L. Zwemer, and W. B. Cannon, “Studies on the Conditions of Activity in Endocrine Glands, XXV: The Mystery of Emotional Acceleration of the Denervated Heart After Exclusion of Known Humoral Accelerators,” American Journal of Physiology 96 (1931): 377–391. An account of this work is also given in Z. M. Bacq, Chemical Transmission of Nerve Impulses: A Historical Sketch (New York: Pergamon, 1975), pp. 38–39.
48. Cannon and Bacq, “Studies, XXVI,” p. 408.
49. The anatomical arrangement of the sympathetic nervous system, with its chain of ganglia that permits vertical communication between different nerves, facilitates the triggering of the system as a whole (see fig. 1 above).
50. The preganglionic parasympathetic neurons tend to be long, and they synapse on postganglionic neurons close to or within the organ that is innervated. This anatomical arrangement does not have the same potential for integrating a group of responses that exists in the sympathetic nervous system (see fig. 1).
51. Cannon and Bacq, “Studies, XXVI.”
52. George Parker did much of this work in his seventies. At the age of seventy-six, Parker was awarded a prize by the American Philosophical Society for his studies of the control of adaptive color changes in fish.
53. In a speech given in 1931 Cannon contrasted Parker’s ideas about the origin of the humoral substances with his own and what he mistakenly believed were those of Thomas Elliott. Cannon’s speech was delivered in 1931 to the Association for the Study of Internal Secretions.
54. George Parker published the book Humoral Agents in Nervous Activity, with Special Reference to Chromatophores in 1932 (Cambridge University Press).
55. W. B. Cannon, “Chemical Mediators of Autonomic Nerve Impulses,” Science 78 (1933): 43–48.
56. After Zénon Bacq worked with Cannon, he had an opportunity to work with G. L. Brown in Henry Dale’s department at the National Institute for Medical Research in Hampstead.
57. H.W. Davenport, “Signs of Anxiety, Rage, or Distress,” Physiologist 24 (1981): 3.
58. Davenport, “Signs,” p. 3.
59. N. Wiener, Cybernetics; or, Control and Communication in the Animal and the Machine (Cambridge, Mass.: M.I.T. Press, 1948). In this book Norbert Wiener mentions regularly attending Rosenblueth’s roundtable discussion group, and he acknowledged that the book “represent[ed] the outcome, after more than a decade, of a program of work undertaken jointly with Dr. Arturo Rosenblueth … a colleague and collaborator of the late Dr. Walter B. Cannon.” In 1945 Norbert Wiener and Rosenblueth spent ten weeks together in Mexico City, after the latter had returned to Mexico.
60. A. Rosenblueth, “The Sensitivization by Cocaine of Gastric and Uterine Smooth Muscle to the Inhibitory Action of Adrenin,” American Journal of Physiology 98 (1931): 186–193. Otto Loewi had earlier demonstrated in a different way that prior treatment with cocaine potentiated the response to adrenaline.
61. W. B. Cannon and A. Rosenblueth, “Studies on Conditions of Activity of Endocrine Glands, XXVIII: Some Effects of Sympathin on the Nictitating Membrane,” American Journal of Physiology 99 (1931–1932): 398–407.
62. Cannon, “Chemical Mediators,” pp. 45–46.
63. W. B. Cannon and A. Rosenblueth, “Studies on Conditions of Activity in Endocrine Glands, XXIX: Sympathin E and Sympathin I,” American Journal of Physiology 104 (1933): 557–574. See also Cannon, “Chemical Mediators.”
64. Ergotoxine is one of a number of different alkaloid substances derived from the ergot fungus. They all have marked effects on the uterus and cardiovascular system, in part because of their ability to block peripheral adrenergic activity. See chap. 4 above for an extended discussion.
65. It was well known that adrenaline makes the nictitating membrane contract and the uterus relax. When they tested sympathin obtained by stimulating the hepatic nerve, it had the same effect as adrenaline on the nictitating membrane, but not on the uterus. However, when they obtained the sympathin by stimulating the nerve that innervates the duodenal artery, both contraction of the nictitating membrane and relaxation of the uterus occurred (see Cannon, “Chemical Mediators,” p. 46).
66. Cannon described these ideas about the two sympathins in a review article entitled “The Story of the Development of Our Ideas of Chemical Mediation of Nerve Impulses” (American Journal of Medical Science 188 [1934]: 145–159).
67. Z. Bacq, “Walter B. Cannon’s Contribution to the Theory of Chemical Mediation of the Nerve Impulse,” in Brooks, Koizumi, and Pinkston, eds., Life and Contributions, pp. 73–74.
68. See, for example, H. H. Dale, “The Beginnings and the Prospects of Neurohumoral Transmission,” Pharmacological Reviews 6 (1954): 7–14, esp. p. 7.
69. W. B. Cannon and A. Rosenblueth, Autonomic Neuro-Effector Systems (Experimental Biology Monographs) (New York: Macmillan, 1937).
70. See, for example, Bacq, “Cannon’s Contribution.”
71. A copy of Göran Liljestrand’s review in the Nobel Archives was provided to the author. It should also be noted that Liljestrand was the teacher of Ulf von Euler, who won the Nobel Prize in part for determining that norepinephrine (noradrenaline) is the main neurotransmitter at sympathetic nerve terminals.
72. See B. Cannon, “Walter B. Cannon: Personal Reminiscences,” in Brooks, Koizumi, and Pinkston, eds., Life and Contributions, p. 167.
73. W. B. Cannon, “The Nobel Prize in Physiology and Medicine,” Scientific Monthly 44 (1937): 195–198 (quote from p. 198).
74. Letter from Henry Dale to Walter Cannon, November 15, 1936.
75. Lissák and some collaborators also measured the duration of the diminution of acetylcholine in a nerve after it had been severed and demonstrated that the disappearance of this substance was correlated with the loss of effectiveness of the severed nerve to excite skeletal muscles. Cited in W. B. Cannon, “The Argument for Chemical Mediation of Nerve Impulses,” in M. B. Visscher, ed., Chemistry and Medicine: Papers Presented at the Fiftieth Anniversary of the Founding of the Medical School of the University of Minnesota (Minneapolis: University of Minnesota Press, 1940), pp. 276–291.
76. W. B. Cannon and K. Lissák, “Evidence for Adrenaline in Adrenergic Neurons,” American Journal of Physiology 125 (1939): 765–785.
77. Cannon and Lissák, “Evidence,” p. 774.
78. R.P. Ahlquist, “A Study of the Adrenergic Receptors,” American Journal of Physiology 153 (1948): 586–600.
79. Isoproterenol, for example, was effective only at beta sites. Noradrenaline (norepinephrine) primarily acted on alpha receptors, while adrenaline (epinephrine) acted mainly on beta receptors.
80. It was several years before the dual–adrenergic receptor theory was widely accepted. Ahlquist, a pharmacologist, had initially submitted his manuscript to the Journal of Pharmacology and Experimental Therapeutics, but the editor rejected the manuscript mainly because of what was judged to be its audacious and irreverent tone. See G. O. Carrier, “Evolution of the Dual Adrenergic Receptor Concept, Key to Past Mysteries and Modern Therapy,” in M. J. Parnham and J. Bruinvels, eds., Discoveries in Pharmacology, vol. 3: Pharmacological Methods, Receptors, and Chemotherapy (New York: Elsevier, 1986), pp. 217–218.
81. U. S. von Euler, “A Specific Sympathomimetic Ergone in Adrenergic Nerve Fibers (Sympathin) and Its Relations to Adrenaline and Nor-adrenaline,” Acta physiologica scandinavica 12 (1946): 73–97. For historical reflections see U. S. von Euler, “Discoveries of Neurotransmitter Agents and Modulators of Neuronal Functions,” in E. G. Worden, J. P. Swazey, and G. Adelman, eds., The Neurosciences: Paths of Discovery I (Boston: Birkhäuser, 1992), pp. 181–187. In von Euler’s 1946 paper he noted that it had recently been shown that noradrenaline can be formed in the body by demethylation of adrenaline.
82. A. Rosenblueth, The Transmission of Nerve Impulses at Neuroeffector Junctions and Peripheral Synapses (New York: Wiley, 1950).
83. Dale, “Beginnings,” p. 8.
84. H. H. Dale, “Chemical Transmission of the Effects of Nerve Impulses,” British Medical Journal, May 12, 1934, 835–841 (quote from p. 837.)
85. H. H. Dale, Adventures in Physiology (London: Pergamon, 1953), p. 98.
86. Bacq, Chemical Transmission.
87. U. von Euler, Noradrenaline: Chemistry, Physiology, Pharmacology, and Clinical Aspects (American Lecture Series 261) (Springfield, Ill.: Charles Thomas, 1965), p. 4.
CHAPTER 8
1. J. C. Eccles, “Synaptic and Neuromuscular Transmission,” Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie 38 (1936): 339–444 (quote from p. 397).
2. Z.M. Bacq, Chemical Transmission of Nerve Impulses: A Historical Sketch (New York: Pergamon, 1975), p. 51.
3. Z.M. Bacq, “Chemical Transmission of Nerve Impulses,” in M. J. Parnham and J. Bruinvels, eds., Psycho- and Neuro-Pharmacology (New York: Elsevier, 1983), pp. 92–93.
4. In a later account, after he had already changed his mind, John Eccles noted the opposition to chemical transmission expressed by his fellow neurophysiologists at a 1939 symposium on the synapse. He wrote that at the meeting “Lorente de Nó, [Herbert] Gasser and [Joseph] Erlanger were strongly in favor of electrical transmission” (J. Eccles, The Physiology of Synapses [New York: Academic Press, 1964]).
5. J. Erlanger, “The Initiation of Impulses in Axons,” Journal of Neurophysiology 2 (1939): 370–379 (quote from p. 371).
6. D. Bronk, “Synaptic Mechanism in Sympathetic Ganglia,” Journal of Neurophysiology 2 (1939): 380–401 (quote from p. 382).
7. J. S. Cook, “‘Spark’ vs. ‘Soup’: A Scoop for Soup,” News in Physiological Sciences 1 (1986): 206–208.
8. Both letters are cited in In Memory of Sir Henry Dale, Sir Paul Girolami, Lady Helena Taborikova, and Guiseppi Nitisco, eds. (Accademeia Roma di Scienze Mediche e Biologiche).
9. Cited in In Memory of Sir Henry Dale.
10. Cited in In Memory of Sir Henry Dale
11. See Eccles’ letter dated July 28, 1943, and Dale’s reply dated August 22 in In Memory of Sir Henry Dale.
12. In 1966 John Eccles came to the United States, taking a position at the American Medical Association’s Institute for Medical Research in Chicago. In 1968 he moved to the State University of New York at Buffalo, where he remained until retiring in 1975 at the age of seventy-two. Eccles then moved to Switzerland, where he died at the age of ninety-four. During the latter years, including the postretirement years, Eccles wrote books on the relation of the brain and mind, the emergence of consciousness, and the concept of the self as well as a work on the evolution of the brain and a biography of Charles Sherrington.
13. W. Feldberg, “The Early History of Synaptic and Neuromuscular Transmission by Acetylcholine: Reminiscences of an Eye Witness,” in A. L. Hodgkin et al., eds., The Pursuit of Nature: Informal Essays on the History of Physiology (Cambridge: Cambridge University Press, 1977), p. 72.
14. J. C. Eccles, “Under the Spell of the Synapse,” in F. G. Worden, J. P. Swazey, and G. Adelman, eds., The Neurosciences: Paths of Discovery I (Boston: Birkhäuser, 1992), p. 161.
15. B. Katz, “Bernard Katz.,” in L. Squires, ed., The History of Neuroscience in Autobiography, vol. 1 (Washington, D.C.: Society for Neuroscience, 1966), p. 373.
16. A.G. Karczmar, “Sir John Eccles, 1903–1907, Part 1: On the Demonstration of the Chemical Nature of Transmission in the CNS,” Perspectives in Biology and Medicine 44 (2001): 81.
17. Feldberg, “Early History,” p. 67.
18. J. C. Eccles, “Synaptic and Neuro-Muscular Transmission,” Physiological Reviews 17 (1937): 538–555.
19. Eccles, “Synaptic and Neuro-Muscular Transmission,” p. 551.
20. W. B. Cannon, “The Argument for Chemical Mediation of Nerve Impulses,” Science 90 (1939): 521–527.
21. Quoted from a similar article published the following year: W. B. Cannon, “The Argument for Chemical Mediation of Nerve Impulses,” in M. B. Visscher, ed., Papers Presented at the Fiftieth Anniversary of the Founding of the Medical School of the University of Minnesota (Minneapolis: University of Minnesota Press, 1940), p. 281.
22. Eccles, “Synaptic and Neuro-Muscular Transmission”; J. F. Fulton, Physiology of the Nervous System (New York: Oxford University Press, 1938).
23. Cannon, “Argument for Chemical Mediation,” p. 527.
24. Eccles, “Under the Spell,” p. 161.
25. Birdsey Renshaw had discovered the role of small “internuncial cells” in creating recurrent inhibition of spinal motor neurons: B. Renshaw, “Influence of Discharge on Motor Neurons Upon Excitation of Neighboring Motor Neurons,” Journal of Neurophysiology 4 (1941): 167–183
26. J. C. Eccles, “From Electrical to Chemical Transmission in the Central Nervous System,” Notes and Records of the Royal Society, London 30 (1976): 219–230 (quote from p. 225).
27. L.G. Brook, J. S. Coombs, and J. C. Eccles, “The Recording of Potentials from Motorneurons with an Intracellular Electrode,” Journal of Physiology 117 (1952): 431–460 (quote from p. 455).
28. In addition to sodium, Hodgkin, Huxley, and Bernard Katz later explained that the resting potential of a neuron also depended on the movement of potassium and chloride ions; see A. L. Hodgkin and A. F. Huxley, “A Quantitative Description of Membrane Current and Its Application to Conduction and Excitation in Nerves,” Journal of Physiology 117 (1952): 500.
29. Eccles and his colleagues were correct in principle, if not in all the details. It is now known that a collateral branch from the spinal motor nerve axon secretes acetylcholine to stimulate the small Renshaw cells, which in turn secrete an inhibitory neurotransmitter.
30. From Eccles’ letter to Dale dated September 17, 1953, cited in In Memory of Sir Henry Dale.
31. Eccles, “From Electrical to Chemical Transmission,” p. 226.
32. H. H. Dale, “The Beginnings and the Prospects of Neurohumoral Transmission,” Pharmacological Reviews 6 (1954): 11.
33. Dale, “Beginnings,” p. 10. Dale was repeating an earlier comment attributed to von Bruecke.
34. H. H. Dale to J. C. Eccles, August 22, 1943, cited in Eccles, “From Electrical to Chemical Transmission,” p. 224.
35. J.F. Fulton, Physiology of the Nervous System, 3d ed. (New York: Oxford University Press, 1949), p. 73.
36. Eccles, “From Electrical to Chemical Transmission,” p. 223; A. Fessard, “Transmissions, synaptiques ganglionnaire et centrale: Discussion,” Acta internat. physiol. 59 (1951): 605–618.
37. C.T. Morgan and E. Stellar, Physiological Psychology (New York: McGraw-Hill, 1950).
38. R.W. Gerard, “Discussion (Symposium on Neurohumoral Transmission, Physiological Society of Philadelphia, Sept. 11–12, 1953,” Pharmacological Reviews 6 (1954): 123–131 (quote from p. 123; see also p. 126).
39. A. K. McIntyre, “Central and Sensory Transmission (Symposium on Neurohumoral Transmission, Physiological Society of Philadelphia, Sept. 11–12, 1953),” Pharmacological Reviews 6 (1954): 103–104 (quote from p. 103).
40. W. S. Feldberg, “Transmission in the Central Nervous System and Sensory Transmission (Symposium on Neurohumoral Transmission, Physiological Society of Philadelphia, Sept. 11–12, 1953),” Pharmacological Reviews 6 (1954): 85–93 (quotes from p. 85).
CHAPTER 9
1. “Austrian Receives Award. Clerical Press Plays Down Nobel Award to Jewish Scientist,” New York Times, November 2, 1936, p. 12.
2. From “An Autobiographical Sketch,” reprinted in F. Lembeck and W. Giere, Otto Loewi: Ein Lebensbild in Dokumenten (Berlin: Springer, 1968), pp. 185–186.
3. The concerted effort made by Henry Dale and Walter Cannon to help Otto Loewi is well documented in E. L. Wolfe, A. C. Barger, and S. Benison, Walter B. Cannon: Science and Society (Cambridge, Mass.: Harvard University Press, 2000), pp. 386–392.
4. As cited in Wolfe, Barger, and Benison, Science and Society, p. 387.
5. Loewi’s Nobel Prize money had to be transferred to a German bank. According to the Nobel records, in 1939 Loewi was awarded a grant of 5,000 Swedish crowns for his research in consideration of the money he had had to surrender to the Germans.
6. Z.M. Bacq, Chemical Transmission of Nerve Impulses: A Historical Sketch (New York: Pergamon, 1975), p. 99.
7. See discussion in Wolfe, Barger, and Benison, Science and Society, pp 388–392.
8. O. Loewi, “An Autobiographical Sketch,” Perspectives in Biology and Medicine 4 (1960): 23.
9. O. Loewi, From the Workshop of Discoveries (Porter Lecture Series 19) (Lawrence: University of Kansas Press, 1953).
10. Reported in D. Lehr, “The Life and Work of Otto Loewi,” Medical Circle 9 (1962): 126–131.
11. Bacq, Chemical Transmission, p. 100.
12. William van der Kloot (1990), as cited in a personal communication by H. Davenport in “Early History of the Concept of Chemical Transmission of the Nerve Impulse,” Physiologist 34 (1991): 185–186. William van der Kloot was Loewi’s colleague at New York University.
13. J. H. Gaddum, “Prof. Otto Loewi,” Nature 193 (1962): 525–526.
14. Quoted in the New York Times (Dec. 27, 1961, p. 21, col. 1) obituary for Otto Loewi.
15. O. Loewi, “A Scientist’s Tribute to Art,” in Essays in Honour of Hans Tietze, 1880–1954 (New York: Gazette de Beaux Arts, 1958), pp. 389–392.
16. Cited in W. Feldberg, “Henry Hallett Dale, 1875–1968,” Royal Society Obituaries and Memoirs, 1830–1998 16 (1970): 77–174 (quote from p. 159).
17. Letter from Dale to Eccles, August 25–26, 1954, cited in J. C. Eccles, “From Electrical to Chemical Transmission in the Central Nervous System,” Notes and Records of the Royal Society, London 30 (1976): 219–230 (letter cited p. 228).
18. A complete list of Dale’s publications is provided in Feldberg, “Henry Hallett Dale, 1875–1968.”
19. Cited in Feldberg, “Henry Hallett Dale, 1875–1968,” pp. 152–153.
20. Cited in “Obituary: Henry Hallett Dale,” Lancet, August 3, 1968, 288–290.
21. H. Dale, “The Atomic Problem Now,” Spectator, September 30, 1949, 409.
22. H. Dale, “What Nagasaki Meant,” Spectator, July 13, 1951, 54–55.
23. “Obituary: Henry Hallett Dale,” Lancet, August 3, 1968, 288–290.
24. Quoted from a letter dated January 22, 1940, cited in Wolfe, Barger, and Benison, Science and Society, p. 447.
25. Cannon had also intervened in mobilizing support for Pavlov, when, following the Russian Revolution in 1917, there were somewhat exaggerated (as it turned out) reports that Pavlov was starving in St. Petersburg. They first met when Pavlov visited the United States in 1922, and they met again at the International Congress of Physiology held in Boston in 1929. The two had a warm reunion, and Cannon took Pavlov to his summer house in Franklin, New Hampshire, where he met with much of the Cannon family. The third meeting between Cannon and Pavlov was at the congress in Leningrad in August 1935.
26. When Cannon arrived in Shanghai with his family, they were greeted by Dr. J. H. Liu, who had been Cannon’s student at Harvard in 1915. Cannon, who always prepared diligently for talks, gave lectures at the National Medical College in Shanghai and at the Army Medical College in Nanking. In addition, he gave several public lectures on the physiology of emotions and the importance of a prepared mind in scientific research. Cannon received enthusiastic applause after all his lectures. His wife was also invited to lecture about her work with the Birth Control League of Massachusetts, and wherever they traveled in China she made contact with people involved in the birth control movement. In Peking (now Beijing) they were greeted at the railroad station by the entire physiology department of the Peking Union Medical College. Cannon gave three lectures a week at P.U.M.C., talking about the chemical mediation of nerve impulses, the physiology of emotions, sham rage, and homeostasis. The lectures were so well attended that there was only standing room and many could not even get into the room. He also worked in the laboratory, starting experiments on denervation sensitivity with some of the staff and students and demonstrating his technique for performing a total sympathectomy.
Cannon was kept so busy in China that Cornelia wrote in a letter home: “He might as well be in Cambridge for, except for the rickshaw ride to the P.U.M.C. every day and weekends in the country, he sees only rheostats and smoked drums and the insides of cats.” His hosts gave him a Chinese name that captured what they regarded as his main traits—friendliness and diligence. Later, after returning to Harvard, Cannon accepted a Chinese student from the P.U.M.C. to work in his laboratory.
The Cannons also visited the Japanese University of Mukden, where Cannon enjoyed his time with Professor Kuno, a gentle Japanese scholar whose friendliness to the Chinese was a sharp contrast to the swaggering Japanese military Cannon had seen on brief visits to Manchuria and also Korea.
27. V. M. Molotov’s official position at the time was chairman of the council of the people’s commissars.
28. Some details of Cannon’s medical condition and the eventual cause of his death are described in R. Spillman, “Editorial: Walter Bradford Cannon, 1871–1945,” American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine 55 (1946): 94–96. According to Spillman’s account, Cannon’s severe itching was caused by leukemia cutis (mycosis fungoides), and his eventual death was due to malignant lymphoma.
29. W. B. Cannon and A. Rosenblueth, Autonomic Neuro-Effector Systems (Experimental Biology Monographs) (New York: Macmillan, 1937).
30. W. B. Cannon, The Mechanical Factors of Digestion (London: Arnold, 1911); W. B. Cannon, Bodily Changes in Pain, Hunger, Fear, and Rage: An Account of Recent Researches Into the Function of Emotional Excitement (New York: Appleton, 1915); W. B. Cannon, A Laboratory Course in Physiology (Cambridge, Mass.: Harvard University Press, 1923): W. B. Cannon, Traumatic Shock (New York: Appleton, 1923): W. B. Cannon, The Wisdom of the Body (New York: Norton, 1932); W. B. Cannon, Digestion and Health (New York: Norton, 1936).
31. Cannon first used the term “homeostasis” in a 1925 speech honoring Charles Richet. A paper based on the speech, entitled “Physiological Regulation of Normal States: Some Tentative Postulates Concerning Biological Homeostatics,” was published the following year (Transactions of the Congress of American Physicians and Surgeons 12 [1926]: 91). He next delivered a lecture to psychiatrists and neurologists in New York entitled “The Sympathetic Division of the Autonomic Nervous System in Relation to Homeostasis.” Shortly afterward, Cannon gave a lecture in Chicago entitled “Functions of the Sympathetic Nervous System in Maintaining the Stability of the Organism.” This idea was more fully described and illustrated in a review article entitled “Organization for Physiological Homeostasis” (Physiological Reviews 9 [1929]: 399–431) and in two articles published in 1930, the Linacre Lecture in Cambridge and one at the Sorbonne.
In his book Cybernetics; or, Control and Communication in the Animal and the Machine (New York: M.I.T. Press 1961), p. 115 and elsewhere, Norbert Wiener acknowledges his indebtedness to Cannon and the concept of homeostasis.
32. Cannon was writing during the 1930s, when there was a worldwide depression and war was imminent in several parts of the world. He wrote that it was time to consider whether the wars and famines, the inequalities in distribution, and the economic swings that lead to periods of “boom and bust” and depressions might be avoided or ameliorated if some protective, stabilizing mechanisms were in place.
33. W. B. Cannon, The Body as a Guide to Politics (Thinker’s Forum 15) (London: Watts, 1942).
34. Cannon argued that stabilizing mechanisms in the social realm would enhance, not curtail, freedom, just as the automatic regulation of the internal environment of the body frees an organism to engage in other activities. People in dire economic straits, Cannon wrote, are not truly free men, and he quoted the lord chancellor of England who had declared that “Necessitous men are not, truly speaking, free men.” Cannon elaborated on the many different types of social upheavals that can impose severe hardships on individuals. He noted that: “A new machine may be invented which, because it can do the work of thousands of laborers, throws thousands of laborers out of their jobs and in such disasters individual members of the social organization are not responsible for the ills which circumstances forces them to endure.”
Only thoughtful advance planning, he argued, could ameliorate these social and economic problems: “Various schemes for avoidance of economic calamities have been put forth not only by dreamers of Utopias but also by sociologists, economists, statesmen, labor leaders, and experienced managers of affairs…. Communists have offered their solution of the problem and are trying out their ideas on a large scale in the Soviet Union. The socialists have other plans for the mitigation of the economic ills of mankind. And in the United States where neither communism or socialism has been influential, various suggestions have been offered for stabilizing the conditions of industry and commerce…. The multiplicity of these schemes is itself proof that no satisfactory social scheme has been suggested by anybody. The projection of the schemes, however, is clear evidence that in the minds of thoughtful and responsible men a belief exists that intelligence applied to social instability can lessen the hardships which result from technological advances, unlimited competition and the relatively free play of selfish interests.”
Today, when Republicans seem to favor an unfettered, free market economy, it will surprise many that Cannon, who favored economic restraints and planning and advocated “New Deal” policies before there was a “New Deal,” always voted for Republican presidents. Cannon never voted for Franklin Roosevelt despite the fact that his son-in-law, Arthur M. Schlesinger Jr., an advisor to Roosevelt, tried unsuccessfully to persuade him that he and the president held similar views.
35. W. B. Cannon, The Way of an Investigator: A Scientist’s Experiences in Medical Research (New York: Norton, 1945).
36. A. J. Carlson, review of The Way of an Investigator, in Scientific Monthly, October 1945, p. 117.
37. The quote is from the report Cannon wrote as chairman of the subcommittee responsible for summarizing the mission of the NRC Committee for Research on the Study of Sex. The full report is available in the Archives of the National Academy of Sciences, U.S.A.
38. B. Cannon, “Walter B. Cannon: Personal Reminiscences,” in C. M. Brooks, K. Koizumi, and J. O. Pinkston, eds., The Life and Contributions of Walter Bradford Cannon, 1871–1945 (New York: State University of New York, Downstate Medical Center, 1975), p. 162.
39. When Kinsey’s books were attacked by some congressmen, the Rockefeller Foundation withdrew its support in 1954.
40. W. B. Cannon, “‘Voodoo’ Death,” American Anthropologist 44 (1942): 169. Reprinted in Psychosomatic Medicine 19 (1957): 182–190.
41. Today the emphasis would be on the role of stress in triggering responses from a circuit including the hypothalamus and pituitary and adrenal cortical hormones. See E. M. Sternberg, “Walter B. Cannon and ‘Voodoo Death’: A Perspective from Sixty Years On,” American Journal of Public Health 92 (2002): 1564–1565.
42. C.P. Richter, “The Phenomenon of Sudden Death in Animals and Man,” Psychosomatic Medicine 19 (1957): 191–198. In one series of experiments, Richter demonstrated that severe stress shortened the survival time of animals placed in extreme conditions.
43. W. B. Cannon, “Law of Denervation (Hughlings Jackson Memorial Lecture),” American Journal of Medical Science 198 (1939): 737–750.
44. Philip Bard’s letter is dated December 15, 1939. It is quoted as cited in Wolfe, Barger, and Benison, Science and Society, p. 475.
45. The book is W. B. Cannon and A. Rosenblueth, The Supersensitivity of Denervated Structures: A Law of Denervation (New York: Macmillan, 1949). Of its twenty-two chapters, eleven were completely finished by Cannon, and these appeared in the final version essentially as he had written them. Rosenblueth finished five chapters that Cannon had not completed and wrote six additional chapters.
46. H. H. Dale, “Prof. W. B. Cannon,” Nature 158 (July 20, 1946): 87–88.
47. Bacq, Chemical Transmission, pp. 100–101.
48. R. Levi-Montalcini, In Praise of Imperfection: My Life and Work (New York: Basic Books, 1988).
49. O. Loewi, “Salute to Henry Hallett Dale,” British Medical Journal, 1955, p. 1357.
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1. E. Roberts, “GABA and Inhibition: Command Control in Nervous System Function,” in F. Samson and G. Adelman, eds., The Neurosciences: Paths of Discovery II (Boston: Birkhäuser, 1992), p. 92.
2. Chang and Gaddum had reported finding acetylcholine in the brain, as well as other organs, in six different species. See H. C. Chang and J. Gaddum, “Choline Esters in Tissue Extracts,” Journal of Physiology, London 79 (1933): 255–285.
3. Z.M. Bacq, “Chemical Transmission of Nerve Impulses,” in M. J. Parnham and J. Bruinvels, eds., Psycho- and Neuro-Pharmacology (New York: Elsevier, 1983), p. 88.
4. W. Feldberg and M. Vogt, “Acetylcholine Synthesis in Different Regions of the Central Nervous System,” Journal of Physiology, London 107 (1948): 372–381.
5. J.D. Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (1890–1990) (New York: Oxford University Press, 2001), pp. 75–76.
6. M. Vogt, “The Concentration of Sympathin in Different Parts of the Central Nervous System Under Normal Conditions and After the Administration of Drugs,” Journal of Physiology, London 123 (1954): 451–481.
7. Vogt did note that the distribution of sympathin might suggest that it has a neurotransmitter role, but she then listed a number of reasons to be cautious about drawing that conclusion. For example, it was known that adrenaline and noradrenaline were present in high concentrations in gliomas, where they could not serve as neurotransmitters. She also noted that it was possible that adrenaline and noradrenaline were in the brain to modify transmission of other substances, noting in this context that adrenaline had been reported to modify the response to acetylcholine.
8. W. Feldberg, A Pharmacological Approach to the Brain: From Its Inner and Outer Surfaces (Baltimore: Williams and Wilkin, 1963). See table on p. 42. This book was based on a 1961 lecture presented at Washington University in St. Louis, Missouri.
9. Feldberg explained his results by assuming that the anesthetic had paralyzed the hypothalamic region that B. K. Anand and John Brobeck had called the “satiety center” because its destruction produced animals that exhibited almost insatiable eating. B. K. Anand and J. R. Brobeck, “Hypothalamic Control of Food Intake in Rats and Cats,” Yale Journal of Biology and Medicine 24 (1951): 123–140. Feldberg, Pharmacological Approach, p. 55.
10. Feldberg, Pharmacological Approach, pp. 106–107.
11. J. H. Gaddum, “Chemical Transmission in the Central Nervous System,” Nature 197 (1963): 742.
12. The affection and respect that the young scientists working with Feldberg had for him is reported in Bacq, “Chemical Transmission,” pp. 100–101. A similar account was given by Robert Myers (personal communication, August 30, 2001), a young American scientist who had the opportunity to work with Wilhelm Feldberg.
13. Personal communication from David Longley, November 19, 2003.
14. Animal rights activists had gained access to his laboratory under the pretext of making a film of his research. Parts of the film were submitted to the Home Office with the accusation that his experimental animals were inadequately anesthetized. Feldberg’s Home Office license was revoked. The report by the Medical Research Council’s enquiry published in 1991 was less critical of Feldberg, although it recognized that some breach of regulations had occurred. This report recommended a “tightening of controls,” but by this time Feldberg had made the decision to retire from laboratory work. A summary of Wilhelm Feldberg’s life and scientific work can be found in Biographical Memoirs of the Royal Society 43 (1997): 145–170.
15. The story of the accidental discoveries of the initial psychotropic drugs is described in E. S. Valenstein, Blaming the Brain: The Truth About Drugs and Mental Health (New York: Free Press, 1998).
16. John Gaddum’s experience with LSD is recounted in D. Healy, The Creation of Psychopharmacology (Cambridge, Mass.: Harvard University Press, 2002), p. 204.
17. J. H. Gaddum, “Drugs Antagonistic to 5-Hydroxytriptamine,” in G. E. W. Wolstenholme and M. P. Cameron, eds., Ciba Foundation Symposium on Hypertension: Humoral and Neurogenic Factors (Boston: Little, Brown, 1954), p. 77. The first report of finding serotonin in the brain appeared in B. M. Twarog and J. H. Page, “Serotonin Content of Some Mammalian Tissues and Urine, and a Method for Its Determination,” American Journal of Physiology 175 (1954): 157–161. It is telling that this paper was originally submitted to another journal in 1952 but was rejected by the editor as unimportant. This incident is reported in B. M. Twarog, “Serotonin: History of a Discovery,” Comparative Biochemistry and Physiology 91 (1988): 21–24. For a brief discussion of the discovery of LSD and its connection to serotonin see Valenstein, Blaming the Brain, pp. 12–15.
18. D.W. Woolley and E. Shaw, “A Biochemical and Pharmacological Suggestion About Certain Mental Disorders,” Science 119 (1954): 587–588. Woolley and Shaw wrote: “pharmacological findings indicate that serotonin has an important role to play in mental process and that the suppression of its action results in a mental disorder. In other words, it is the lack of serotonin which is the cause of the disorder. If now a deficiency of serotonin in the central nervous system were to result from metabolic rather than from pharmacologically induced disturbances, these same mental aberrations would be expected to become manifest. Perhaps such a deficiency is responsible for the natural occurrence of the diseases.”
19. B. B. Brodie, A. Pletscher, and P. S. Shore, “Evidence That Serotonin Has a Role in Brain Function,” Science 122 (1955): 968.
20. S. S. Kety, “Biochemical Theories of Schizophrenia,” Science 129 (1959): 1528–1532; 1590–1596.
21. Kety, “Biochemical Theories.”
22. J. Schildkraut and S. S. Kety, “Biogenic Amines and Emotion: Pharmacological Studies Suggest a Relationship Between Brain Biogenic Amines and Affective State,” Science 156 (1967): 21.
23. A. Carlsson, “A Paradigm Shift in Brain Research,” Science 294 (2001): 1022.
24. Published in J. R. Vane, G. E. W. Wolstenholme, and E. O’Connor, eds., Ciba Foundation Symposium on Adrenergic Mechanisms (Boston: Little, Brown, 1960).
25. Carlsson, “Paradigm Shift,” p. 1024.
26. A. Carlsson, “A Half-Century of Neurotransmitter Research: Impact on Neurology and Psychiatry,” Les Prix Nobel 2000, pp. 242–243. See also A. Carlsson, “Arvid Carlsson,” in L. Squire, ed., The History of Neuroscience in Autobiography, vol. 2 (San Diego: Academic Press, 1998), pp. 30–66.
27. H. McLennan, Synaptic Transmission (Philadelphia: Saunders, 1963).
28. N. E. Miller, “Chemical Coding of Behavior in the Brain,” Science 148 (1965): 330.
29. B. Colier and J. E. Mitchell, “The Central Release of Acetylcholine During Stimulation of the Visual Pathway,” Journal of Physiology, London 184 (1966): 239–254. Also see B. Colier and J. E. Mitchell, “The Central Release of Acetylcholine During Consciousness and After Brain Lesions,” Journal of Physiology, London 188 (1967): 83–98.
30. The development of the fluorescent stains and their use have been described in A. Carlsson, “Perspectives on the Discovery of Central Monoaminergic Neurotransmission,” Annual Review of Neuroscience 10 (1987): 19–40.
31. Electrophoresis entails the use of electricity to move molecules in a controlled direction.
32. D. R. Curtis and R. Eccles, “The Excitation of Renshaw Cells by Pharmacological Agents Applied Electrophoretically,” Journal of Physiology, London 141 (1958): 435–445.
33. J. Gaddum, “Push-Pull Cannulae,” Journal of Physiology, London 155 (1961): 1–2.
34. In some of the initial experiments with push-pull cannulae, the acetylcholine secreted by central nervous system neurons was detected by the leech muscle technique.
35. J. H. Gaddum, “Push-Pull Cannulae,” Journal of Physiology, London 153 (1960): 1P–2P.
36. An angstrom (Å) is equal to one ten-millionth of a millimeter. There are approximately 25 millimeters in an inch. George Palade and Sanford Palay first presented these results at the 1954 meeting of the American Association of Anatomists in Galveston, Texas. G. Palade and S. Palay, “Electron Microscope Observations of Interneuronal and Neuromuscular Synapses,” Anatomical Record 118 (1954): 335–336.
37. S. Palay, “Synapses in the Central Nervous System,” Journal of Biophysical and Biochemical Cytology 2.4, suppl. (1956): 193–201.
38. V.P. Whittaker, “The Isolation and Characterization of Acetylcholine-Containing Particles from the Brain,” Biochemical Journal 72 (1959): 694–702.
39. T. Hökfelt, “Electron Microscope Studies on Peripheral and Central Monoamine Neurons” (thesis, Karolinska Inst., Stockholm, 1968). For more details of the early investigations with the electron microscope see Robinson, Mechanisms, pp. 106–112. What was in the synaptic vesicles was later determined by a chemical analysis of the synaptosomes, the terminals that contain the vesicles. The synaptosomes were separated from the rest of the cell by using a centrifuge. Through several steps, it was possible to concentrate the synaptosomes based on differences in weight from other parts of the neuron. A chemical analysis then could determine if the candidate substance was concentrated in the region of the neuron containing the synaptic vesicles.
40. J. C. Eccles, The Inhibitory Pathway of the Central Nervous System (Sherrington Lectures 9) (Springfield, Ill.: Charles Thomas, 1969), p. 112.
41. M. H. Aprison and R. Werman, “The Distribution of Glycine in Cat Spinal Cord and Roots,” Life Sciences, 1965, 2075–2083.
42. Glutamate was first discovered in crayfish in the 1950s, and in the 1960s electrophoretic studies demonstrated that it was effective on mammalian brain neurons.
43. Susan E. Leeman is credited with isolating and characterizing the peptide Substance P: M. M. Chang and S. E. Leeman, “Isolation of a Sialogogic Peptide from Bovine Hypothalamus Tissue and Its Characterization as Substance P,” Journal of Biological Chemistry 245 (1970): 4784–4790.
44. For a good review of the study of histamine in the brain, see R. S. Feldman, J. S. Meyer, and L. F. Quenzer, Principles of Neuropsychopharmacology (Sunderland, Mass: Sinauer, 1997), pp. 445–454.
45. For more of the history of the discovery of the reuptake mechanism, see S. Snyder, “Forty Years of Neurotransmitters,” Archives of General Psychiatry 59 (2002): 983–994.
46. Bernard Katz was born in Leipzig, Germany, in 1911. He was the son of a Russian-Jewish fur trader. In 1935, after experiencing a number of anti-Semitic incidents, he left Germany. He had read a paper by the British physiologist Archibald V. Hill, whose own interest in how muscles are innervated was stimulated by John Langley. Hill, a 1922 Nobel Laureate, was a strong critic of Hitler. When Katz showed up on his doorstep as a refugee from Hitler, Hill decided to take a chance on him. Katz worked with Hill in London and later with John Eccles in Sydney. He returned to England (University College, London) with a Royal Society fellowship arranged by Hill. Bernard Katz was knighted in 1966. He died in 2003 at the age of ninety-two. See obituary, New York Times, April 25, 2003, p. A31.
47. Henry Dale and George Barger may actually have been the first to use the word “receptor,” but, ironically, they criticized the concept as unnecessary, offering other explanations of how a drug might have different effects. See G. Barger and H. H. Dale, “Chemical Structure and Sympathomimetic Action of Amines,” Journal of Physiology, London 41 (1910): 21.
48. In 1894 Emil Fischer, who was awarded a Nobel Prize in 1902 for his work on the cleavage of sugars by enzymes, introduced the analogy of a “lock and key” as a way of thinking about the specificity of chemical reactions. E. Fischer, “Einfluss der Configuration auf die Wirkung der Enzyme,” Berichte der deutschen chemischen Gesellschaft 27 (1894): 2985–2993.
49. Dale’s reservations about the concept of receptors are noted in the reminiscences of W. Patton, in “On Becoming and Being a Pharmacologist,” Annual Review of Pharmacology 26 (1986): 10.
50. R. Miledi, P. Molinoff, and L. T. Potter, “Isolation of the Cholinergic Receptor Protein of the Torpedo Electric Organ,” Nature 229 (1971): 554–557.
51. Snyder, “Forty Years”; S. H. Snyder and G. V. Pasternak, “Historical Review: Opioid Receptors,” Trends in Pharmacological Sciences 24 (2003): 198–205.
52. Receptor binding studies can be done either by combining the radioactive ligand with a homogenate of brain tissue or by placing it on a thin slice of brain mounted on a glass slide. The latter technique has the advantage of preserving some of the anatomical relationships and of using different radioactive ligands on adjacent brain sections.
53. A good description of radioligand binding is presented in Feldman, Meyer, and Quenzer, Principles of Neuropharmacology, pp. 43–51.
54. C. Pert and S. Snyder, “Opiate Receptor Demonstration in Nervous Tissue,” Science 179 (1973): 1011–1014.
55. L. Terenius, “Stereospecific Interaction Between Narcotic Analgesics and a Synaptic Plasma Membrane Fraction of Rat Cerebral Cortex,” Acta pharmacologica et toxicologica 32 (1973): 317–320; E. J. Simon, J. M. Hiller, and I. Edelman, “Stereospecific Binding of the Potent Narcotic Analgesic (3H) Etorphine to Rat Brain Homogenate,” Proceedings of the National Academy of Sciences of the United States of America 70 (1973): 1947–1949.
56. This statement was made in the early 1970s by Avram Goldstein at Stanford University.
57. Before they adopted the mouse vas deferens test for detecting the presence of morphine-like substances, Hughes and Kosterlitz had been using the guinea pig ileum as a bioassay.
58. An account of John Hughes’ trips to the slaughterhouse is given in J. Goldberg, Anatomy of a Scientific Discovery (New York: Bantam Books, 1988), chap. 1.
59. J. Hughes, “Isolation of an Endogenous Compound from the Brain with Pharmacological Properties Similar to Morphine,” Life Sciences 88 (1975): 155–160; J. Hughes, T. Smith, H. Kosterlitz, L. Fothergill, B. Morgan, and H. Morris, “Identification of Two Related Pentapeptides from the Brain with Potent Opioid Agonist Activity,” Nature 258 (1975): 577–579.
60. The test involved stimulating the sympathetic nerve, which caused the vas deferens to contract. Morphine and other opioids blocked the sympathetic response. It was later learned that the opioids blocked the sympathetic release of noradrenaline.
61. H. Kosterlitz and J. Hughes, “Some Thoughts on the Significance of Enkephalin, the Endogenous Ligand,” Life Sciences 17 (1975): 91–96 (quote from p. 95).
62. For additional references see R. Simantov and S. Snyder, “Morphine-Like Peptides in Mammalian Brain: Isolation, Structure Elucidation, and Interactions with the Opiate Receptor,” Proceedings of the National Academy of Sciences of the United States of America 73 (1975): 2515–2519; R. Simantov, A. M. Snowman, and S. Snyder, “A Morphine-Like Factor ‘Enkephalin’ in Rat Brain: Subcellular Localization,” Brain Research 107 (1976): 650–657. To locate the met-enkephalin receptor Snyder and his collaborators used the antibody-immunohistological technique.
63. P. Greengard, “The Neurobiology of Slow Synaptic Transmission,” Science 294 (2001): 1024–1030.
64. The excitatory fast transmission normally uses glutamate as the transmitter; the fast inhibitory transmission generally uses GABA as the neurotransmitter.
65. T. Fukada and T. Kosaka, “Gap Junctions Linking the Dendritic Network of GABAergic Neurons in the Hippocampus,” Journal of Neuroscience 20 (2000): 1519–1528.
66. S. K. Kulkarni and A. C. Sharma, “Nitric Oxide: A New Generation of Neurotransmitter,” Indian Journal of Pharmacology 25 (1993): 14–17; S. H. Snyder and C. D. Ferris, “Novel Neurotransmitters and Their Neuropsychiatric Relevance,” American Journal of Psychiatry 157 (2000): 1738–1751.
67. H. Son, R. D. Hawkins, M. K. Kiebler, P. L. Huang, M. C. Fishman, and E. R. Kandel, “Long-Term Potentiation Is Reduced in Mice That Are Doubly Mutant in Endothelial and Neuronal Nitric Oxide Synthase,” Cell 87 (1996): 1015–1023.
68. The evidence has been reviewed in Snyder and Ferris, “Novel Neurotransmitters.”
69. Snyder and Ferris, “Novel Neurotransmitters,” p. 1748.
70. Personal communication to the author, January 19, 2004.
71. The estimate of 50–100 neurotransmitters includes acetylcholine, the biogenic amines (epinephrine, norepinephrine, serotonin, dopamine, histamine), amino acids, peptides, gasses such as nitric acid and carbon monoxide, and also neuromodulators. See Snyder and Ferris, “Novel Neurotransmitters.” The number of receptors change so often that any number mentioned is likely to be outdated before this book sees the light of day. At the time of writing it is generally agreed that there are six different dopamine receptors and five different classes of serotonin receptors. Moreover, some of these receptors have several subtypes; counting subtypes, then, there are as many as fifteen different serotonin receptors. In addition to the receptors that exist on postsynaptic neurons, there are so-called autoreceptors on presynaptic neurons that modify the rate of release of the neurotransmitter.
72. Paramecia, for example, have an oral groove that serves as a mouth and cilia, hairlike protoplasmic processes that cover most of their bodies. The cilia propel paramecia toward food and then sweep the food into the oral groove. The cilia also sweep harmful substances away, while also propelling the animals out of danger. Jennings observed that the responses of animals without a nervous system are not machinelike and invariable. He noted that the responses of these animals change with their state, such as when they last received food or whether previous experience with a given stimulus was beneficial or harmful. Because a paramecium changes its response to stimuli depending on experience, Jennings concluded that these animals have some capacity for memory and learning. Moreover, because he noted that a given chemical stimulus does not evoke the same response from all parts of a protozoan’s body, he concluded that the responses must be determined by the “release of certain forces already in the organisms.” This is similar to Langley’s proposing the concept of “receptor substances” in order to explain why adrenaline has different effects on different organs in mammals.
Jennings also argued that protozoa respond to all the different classes of stimuli that regulate the behavior of animals with nervous systems. For example, paramecia respond to chemical, temperature, mechanical, light, water pressure, gravity, and electrical stimuli. The following is an often-cited statement by Jennings:
“The writer is absolutely convinced, after a long study of this organism, that if Amoeba were a large animal, so as to come within the everyday experience of human beings, its behavior would at once call forth the attribution to it of stages of pleasure and pain, of hunger, desire, and the like, on precisely the same basis as we attribute these things to a dog…. In conducting objective investigations we train ourselves to suppress this impression, but thorough investigation tends to restore it stronger than at first” (H. S. Jennings, Behavior of the Lower Organisms [Bloomington: University of Indiana Press, 1962], p. 336).
It is of some interest that early in his research career, Henry Dale also studied the behavior of paramecia (H. H. Dale, “Galvanotaxis and Chemotaxis of Ciliate Infusoria,” Journal of Physiology 26 [1901]: 291–361.)
73. The development of a vascular system made it possible for chemicals to circulate more efficiently around the body. With the development of specialized secretory cells that coalesced into glands, hormones secreted into the vascular system provided an additional route for chemical communication. However, although the vascular system increased the efficiency of chemical diffusion, nerve conduction combined with neurotransmitter secretion is many times faster.
74. For example, alpha and beta adrenergic receptors and also receptors for dopamine, serotonin, acetylcholine, glutamate, GABA, and many peptides have been found in bacteria, yeast, and protozoa. It is thought that many of the major neurotransmitter receptor classes were present even before there were animals.
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1. Cited in the New York Times, September 14, 2003, sec. 6, p. 46.
2. Darwin’s theory of natural selection of inherited differences was critical for understanding how species evolved. He had no basis for understanding how inherited differences are transmitted, however, and he never abandoned the Lamarkian theory that acquired characteristics are inherited.
3. W. D. Hamilton, “The Genetic Evolution of Social Behavior,” Journal of Theoretical Biology 7 (1964): 1–52. The concept of inclusive fitness makes evolutionary sense of altruistic behavior and various social behaviors that can favor risking survival to support close relatives (kin), with whom many genes are shared.
4. For example, Paul Greengard has described one of the many factors that influence the amount of neurotransmitter released. Greengard described two different pools of synaptic vesicles: a pool located close to or against the axon terminal, and a reserve pool located at a distance from the terminal. The neurotransmitter is released only from the pool close to the terminal membrane, but the ratio of reserve to releasable pools constantly changes in response to physiological demands on the cell. P. Greengard, F. Valtorta, A. J. Czernik, and F. Benfenati, “Synaptic Vesicles, Phosphoproteins, and Regulation of Synaptic Function,” Science 259 (1993): 780–781.
5. The three other Nobel Laureates who did a substantial amount of their work in Burroughs Wellcome Laboratories were George H. Hitchings, Gertrude Belle Elion, and John R. Vane.