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Blood and hemoglobin: The evolution of knowledge of functional adaptation in a biochemical system

Part I: The adaptation of chemical structure to function in hemoglobin

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References

  1. L. J.Henderson, Blood: A Study in General Physiology (New Haven: Yale University Press, 1928).

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  2. These early developments are well described in the monograph by F. N.Schulz, Die Krystallisation von Eiweisstoffen und ihre Bedeutung für die Eiweisschemie (Jena: Gustav Fischer, 1901).

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  3. See also J. T. Edsall, “Proteins as Macromolecules: An Essay on the Development of the Macromolecule Concept and Some of its Vicissitudes,” Arch. Biochem. Biophys., Supplement I (1962), 12–20.

  4. W.Preyer Die Blutkrystalle (Jena: Mauke's Verlag, 1871).

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  5. Teichmann, Z. rat. Med., 3 (1853), 875; 8 (1858), 141. This reference is taken from Gamgee (see n. 11 below), p. 252.

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  6. The name “hemoglobin” was first proposed by the eminent German physiological chemist Felix Hoppe-Seyler (1825–1895), and was soon universally adopted. See Virchows Arch. path. anat. Physiol., 29 (1864), 223.

  7. For the purposes of this article, it is not necessary to consider the great advances made in the twentieth century in the chemistry of the iron porphyrins and other metalloporphyrins, of which the hemin (in its reduced state now known as heme, or haem) derived from hemoglobin is one. The most notable work in determining the complete structures of these compounds was that of Hans Fischer and his associates in Munich, from about 1920 to 1940. For a survey of the field see, for example, R.Lemberg and J. W.Legge, Haematin Compounds and Bile Pigments: Their Constitution, Metabolism and Function (New York: Interscience Publishers, 1949).

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  8. O.Zinoffsky, “Ueber die Grösse des Hämoglobinmoleküls,” Hoppe-Seylers Z. physiol. Chem., 10 (1886), 16–34.

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  9. A.Jaquet, “Beiträge zur Kenntniss des Blutfarbstoffs,” Hoppe-Seylers Z. physiol. Chem., 14 (1889), 289–296.

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  10. See, for instance, the tabulations in M.Dayhoff, ed., Atlas of Protein Sequence and Structure (Silver Spring, Md.: National Biomedical Research Foundation, 1969). Data for horse hemoglobin are on pages D-43 and D-56. We should note incidentally that Zinoffsky's carbon and hydrogen determinations were apparently much less accurate than his values for iron and sulfur.

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  11. These and other data are summarized in one section of the comprehensive review by ArthurGamgee, “Hemoglobin: Its Compounds and the Principal Products of its Decomposition,” in Textbook of Physiology, E. A.Schäfer, ed., (Edinburgh and London: Young J. Pentland, 1898), I, 185–260. For the discussion of analytical data see pp. 197–203. Gamgee's review gives a valuable picture of the status of knowledge of hemoglobin at the end of the nineteenth century, and I shall have occasion to refer to it again.

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  12. F.Hoppe, “Uber das Verhalten des Blutfarbstoffes im Spectrum des Sonnenlichtes,” Virchow's Arch. path. anat. Physiol., 23 (1862), 446–449. Hoppe, whose father had died when he was nine years old, changed his name to Hoppe-Seyler in 1864, when he was formally adopted as a son by his guardian and brother-in-law, Dr. Seyler. See E. Baumann and A. Kossel, “Zur Erinnerung an Felix Hoppe-Seyler,” Z. physiol. Chem., 21 (1895–96), i–lxii. This biographical memoir also appeared, in essentially identical form, in Ber. Deut. chem. Ges., 28 (1896), 1147–1192. I have referred to him as Hoppe-Seyler in the text.

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  13. G. G.Stokes, “On the Reduction and Oxidation of the Colouring Matter of the Blood,” Proc. Roy. Soc. Lond. 13 (1864), 355–364.

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  14. Ibid., p. 357.

  15. More than sixty years later, in the light of modern electronic concepts of valence, J. B. Conant, in “An Electrochemical Study of Hemoglobin,” J. Biol. Chem., 57 (1923), 401–414, showed that the combination of oxygen with hemoglobin was not an oxidation, as the term is understood today, but an oxygenation, the iron remaining in the ferrous state even after the attachment of oxygen. The true product of oxidation is methemoglobin (ferrihemoglobin), in which the iron is in the ferric state. Methemoglobin in fact does not contain bound oxygen, as earlier workers, from Hoppe-Seyler on, had supposed; the essential change is the loss of an electron from the iron atom during the oxidation. However, we are here concerned with the change in light absorption and in other properties that occurs when hemoglobin binds oxygen reversibly. The earlier use of an incorrect terminology need not mislead us in considering the observed phenomena.

  16. Stokes here cites Funk's Lehrbuch der Physiologie (1863), vol. 1, sec. 108. I have not seen this reference, but Stokes's statement shows that physiological studies on the deoxygenation of blood, as it passes from the arteries to the veins, had already made significant progress. Stokes's paper is a lucid and masterly presentation of some significant experiments and of the conclusions drawn from them. His grasp of the physiological significance of his chemical spectroscopic experiments is impressive, and shows the breadth of his interests. Stokes was Lucasian Professor of Mathematics in the University of Cambridge, and is notable for his law of motion of falling bodies in a viscous medium, for his important work on fluorescence, and for a fundamental theorem in vector analysis, among many other contributions.

  17. A.Rollett, “Physiologie des Blutes und der Blutbewegung,” in Handbuch der Physiologie, L.Hermann, ed. (Leipzig: F. C. W. Vogel. Verlag, 1880), IV, pt. 1, 1–340. For the spectroscopy of hemoglobin see pp. 45–71.

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  18. See above, n. 11.

  19. For references to this early work, one may consult the admirable chapter by Nathan Zuntz, “Blutgase und Respiratorische Gaswechsel,” in L. Hermann's Handbuch der Physiologie, (1882), IV, (pt. 2), 3–162; in this connection see especially pp. 24ff. Zuntz himself had contributed, and in later years continued to contribute, many fundamental observations in this field, and this review of the subject was a masterly portrayal of the problems as they then stood. We shall have more to say of Zuntz's work below.

  20. G.Magnus, “Ueber die im Blute enthaltenen Gase, Sauerstoff, Stickstoff und Kohlensäure,” Poggendorffs Ann. Phys. Chem., 40 (1837), 583–606. Magnus was eminent in his time, and is the subject of an extensive biographical article by his friend August Wilhelm von Hofmann: Zur Erinnerung von vorangegangene Freunde, 3 vols. (Braunschwieg, 1888–89), I, 45–194. Magnus's work on blood is discussed on pp. 89–97.

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  21. For details of the techniques developed, see the article by Zuntz (n. 19), pp. 24–32.

  22. G.Hüfner, “Ueber das oxyhämoglobin das Pferdes,” Hoppe-Seyler's Z. physiol. Chem., 8 (1884), 338–365. The volume of gas is given for standard conditions, i.e., O°C and 1 atmosphere pressure. In this particular study Hüfner actually measured the combination of carbon monoxide, rather than oxygen, with hemoglobin; but the figure for the two gases should be the same. The value of 1.34 cc of gas per gram of hemoglobin corresponds to 32 grams of oxygen per 16,700 grams of hemoglobin, i.e., one gram mole of oxygen per gram atom of iron in hemoglobin.

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  23. See above, n. 8.

  24. See above, n. 9. G. Hüfner, “Neue Versuche zur Bestimmung der Sauerstoffcapacität des Blutfarbstoffs,” Arch. Anat. Physiol. Leipzig (1894), 130, 176. He criticized the views of Bohr, Zentbl. Physiol., 4 242–252, who held that there were several oxyhemoglobins differing in elementary composition and in O2 combining capacity, even in a single sample of blood.

  25. Gamgee (above, n. 11, p. 192) refers to these views of Bohr, only to dismiss them with the statement that Hüfner's later work (1894) had completely refuted Bohr. In the light of present day knowledge, Gamgee's statement appears justified. This was not the last time that Hüfner's conclusions clashed with those of Bohr. In a still more important disagreement between them, shortly to be recounted, Hüfner was wrong and Bohr was right.

  26. P.Bert La Pression Barometrique: recherches de physiologie experimentale (Paris: G. Masson, 1878), pp. 683–697.

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  27. G. Hüfner, “Ueber das Gesetz der Dissociation des Oxyhämoglobins und über einige daran sich knüpfenden wichtigen Fragen aus der Biologie,” Arch. Anat. Physiol. (Physiol. Abtheilung) (1890), 1–27; “Neue Versuche über die Dissociation des Oxyhämoglobins,” Arch. Anat. Physiol., Supplement 5 (1901), 187–217.

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  28. Many authors have defined y as the percentage saturation of the hemoglobin with oxygen, in which case a factor of 100 must be inserted on the right hand side of equations (3) and (4). These units are used in Fig. 1 later in this article.

  29. See, for example, the chapter by M. S.Pembrey on “Chemistry of Respiration” in E. A. Schäfer's Textbook of Physiology (Edinburgh and London: Y. J. Pentland, 1898), I, 692–784. Hüfner's data are discussed on p. 775.

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  30. N.Zuntz, “Ueber den Einfluss des Partialdrucks der Kohlensäure auf die Vertheilung dieses Gases im Blute,” Centralbl. med. Wiss. 5 (1867), 529–533; Beiträge zur Physiologie des Blutes, Inaugural Dissertation (1868), University of Bonn. Alexander Schmidt, Ber. sächs. Akad. Wiss. 19 (1967), 30, made similar observations independently, as Zuntz noted in his later review (n. 19). Zuntz was a major figure in physiology for the next fifty years. In 1910, with Joseph Barcroft and others, he took part in the expedition to Teneriffe to study respiration at high altitudes. I have already referred (n. 19) to his important article in Hermann's Handbuch. For biographical sketches by his associates, see A. Loewy, Berl. klin, Wschr., 57 (1920), 433–435, and A. Durig, Wien klin Wschr., 33 (1920), 344–345.

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  31. For the clearest and most comprehensive statement of Zuntz's views, see his review in Hermann's Handbuch, pp. 64–83. For the reader familiar with modern chemistry, one may formulate Zuntz's proposal in the following equations. Hemoglobin and other proteins, under physiological conditions, are negatively charged; we may denote them by the general symbol P -. To balance their negative charge, equivalent cations (mostly K +) must be present. When CO2 dissolves, it becomes hydrated to H2CO3. Then H2CO -3 +P-⇌HCO- 3+HP. The protein ions thus act as bases, accepting protons from carbonic acid. Zuntz's hypothesis would them assume a joint migration of K+ and HCO3-ions from cells to serum. In fact, of course, the K + ions cannot cross the membrane freely, and electrical neutrality is maintained by inward migration of chloride ions to balance the outward migration of bicarbonate, as discussed below. It was of course impossible for Zuntz in 1867, or in his review, in 1882, to formulate the problem in such terms. It was not until 1887 that Arrhenius published his theory of electrolytic dissociation of acids, bases, and salts, and it required a decade or more after that for physiologists and biochemists to assimilate his views.

  32. H.Nasse, “Untersuchungen über den Austritt und Eintritt von Stoffen (Transudation und Diffusion) durch die Wand der Haargefässe,” Pflügers Arch. ges. Physiol., 16 (1878), 604–634. Nasse had actually reported the essential facts in 1874 at a meeting in Marburg, but noted in his later paper that the findings had aroused little interest. Unfortunately his later paper also was generally ignored.

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  33. H. J.Hamburger, “Ueber den Einfluss der Atmung auf die Permeabilität der Blutkörperchen,” Z. Biol., 28 (1891), 405–416. Hamburger (1859–1924), who was Professor in Groningen, played an important role in introducing the new developments in the physical chemistry of solutions into physiological research. L. J. Henderson's Blood rather surprisingly makes no mention of Hamburger, although Henderson does refer to all the other authors I have discussed here. Hamburger reported on this phenomenon further in a series of later papers.

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  34. R.vonLimbeck, “Ueber den Einfluss des respiratorischen Gaswechsels auf die rothen Blutkörperchen,” Arch. exp. Path. Pharm., 35 (1894), 309–334.

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  35. A.Gürber, “Ueber den Einfluss der Kohlensäure auf die Vertheilung von Basen und Säuren zwischen Serum und Blutkörperchen,” Jber. Fortschr. Tierchem (Maly's Jahresbericht), 25 (1896), 164–167. Gürber, unlike the other investigators mentioned, was aware of Nasse's work and made reference to it.

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  36. This postulate was eventually shown to be incorrect, as we shall see later in Part II of this study. However, it was so close to the truth, for the practical purposes of the workers of the following generation, that it was never challenged until the rise of isotope labeling techniques after 1940.

  37. An exact analysis shows that, if the partial pressure of carbon dioxide actually falls to zero, it should be possible to pump off all the potential CO2, even from a sodium carbonate solution. See for instance, J. T.Edsall and J.Wyman, Biophysical Chemistry (New York: Academic Press, 1958), I, 561–571. However, in practice the available vacuum pumps were obviously unable to approach this theoretical limit.

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  38. See above, n. 19.

  39. F.Holmgren, “Ueber den Mechanismus des Gasaustausches bei der Respiration,” Sitz. Akad. Wiss. Wien., 48 (1863), 614–648; C. Ludwig, Wien. Med. Jahrbuch, 1865, p. 159. The latter paper I have not seen but it is cited by Zuntz (above, n. 19), p. 81 who gives an excellent short discussion. Further references to early work on this subject are given in the notable 1914 paper by Christiansen, Douglas and Haldane (see n. 112), which is discussed in detail later in this article.

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  40. Carl Ludwig was at this time still in Vienna, where he had been professor for ten years, but in 1865 he moved to Leipzig, which was the home of his famous school of physiology for the next twenty years or more.

  41. Zuntz (above, n. 19), p. 81. Translated by the author.

  42. For Bohr's career and scientific achievements, see RobertTigerstedt, “Christian Bohr: Ein Nachruf,” Skand. Arch. Physiol., 25 (1911), ix-xviii; also a briefer but valuable article by L. S. Fridericia in Prominent Danish Scientists, V. Meisen, ed. (Copenhagen, 1932), pp. 173–176.

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  43. This is quoted from a much longer passage in S.Rozental, ed., Niels Bohr: His Life and Work (New York: Interscience Publishers, 1967), p. 11. The description of Christian Bohr on this and the four following pages of Rozental's book gives the best portrayal I have ever seen of his character and personality, to provide a background for the development of his son Niels.

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  44. This passage, in its English translation, is quoted from S. Rozental, ed., Niels Bohr: His Life and Work (New York: Interscience Publishers, 1967), p. 13, and the information in the next paragraph is taken from the same source.

  45. This is an English translation, taken from Fridericia (n. 42, pp. 173–174). The Danish original by Bohr was published in Universitets Festskrift (Copenhagen, 1910). For a longer quotation from Christian Bohr, developing similar thoughts in more detail, see NielsBohr, Atomic Physics and Human Knowledge (New York: John Wiley, 1958), p. 96.

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  46. See n. 22 above.

  47. For references to the papers involved, see Tigerstedt's obituary on Bohr (above, n. 42), and Bohr's own comprehensive summary of his views: C.Bohr, “Blutgase und respiratorischer Gaswechsel” in Handbuch der Physiologie des Menschen, W.Nagel, ed. (Braunschweig, F. Wieweg und Sohn, 1905), I, 54–222. The date of this Handbuch is often given as 1909 but the first half of Vol. I, in which Bohr's chapter appeared, was published in 1905. In connection with Bohr's views we may note that biochemists in very recent years have shown that the blood of normal human individuals does indeed contain several different hemoglobins, which can be separated and purified. However, one of them (hemoglobin A) is present in far larger amount than any of the others. All of them have essentially identical oxygen combining capacity. Thus the modern view, although it bears some superficial resemblance to Bohr's concept of multiple hemoglobins, is really very different. In any case the presence of multiple hemoglobins could not in itself explain the sigmoid form of the oxygen-binding curve of hemoglobin, which is discussed below; indeed the presence of several distinct components, with different oxygen affinities, would tend to make the curve flatter, not steeper.

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  48. See n. 27.

  49. JosephBarcroft, “The Respiratory Function of the Blood, 1st ed. (Cambridge: [Eng.] University Press, 1914), p. 21.

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  50. C.Bohr, K. A.Hasselbalch, and A.Krogh, “Uber einen in biologischen Beziehung wichtigen Einfluss, den die Kohlensäurespannung des Blutes auf dessen Sauerstoff bindung übt” Skand. Arch. Physiol., 16 (1904), 401–412. There was an earlier brief report by the same authors in Zentbl. Physiol., 17 (1904), 661–664, and an article, by Bohr alone, on the theoretical treatment of the oxygen uptake of hemoglobin Zentbl. Physiol., 17 (1904), 682–688.

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  51. A.Kroch, “Apparat und Methoden zur Bestimmung der Aufnahme von Gasen im Blute bei verschiedenen Spannungen der Gase,” Skand. Arch. Physiol., 16 (1904), 390–401.

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  52. A.Krogh, The Anatomy and Physiology of Capillaries, Silliman Lectures (New Haven, Yale University Press, 1922); revised and enlarged edition (1929).

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  53. See Bohr's paper in Zentbl. Physiol., cited in n. 50 above. It is worth noting that later, in 1910, Krogh challenged one of bohr's most firmly held views: namely, that the alveolar cells of the lungs can actively secrete oxygen, against a pressure gradient, from the alveolar air into the lung capillaries, and that they could similarly secrete CO2 in the opposite direction (see Bohr's review in Nagel's Handbuch, pp. 142–160). Krogh, in a series of studies on rabbits reported in Skand. Arch. Physiol., 23 (1910), 179–260, concluded that Bohr was wrong, and that all respiratory exchange in the lung could be accounted for by simple diffusion. He paid a warm tribute to Bohr as his great teacher, to whom he was profoundly indebted, but unequivocally rejected Bohr's conclusions on this question. The controversy over secretion in the lungs continued, however, for J. S. Haldane upheld the view that secretion does occur after adaptation to high altitudes and to other conditions of stress, whereas Barcroft and others concluded that diffusion was adequate to explain all the facts. See J. S. Haldane, Respiration (New Haven: Yale University Press, 1922); 2nd ed. by Haldane and J. G. Priestley (1935); and J. Barcroft, “Lessons from High Altitudes,” in The Respiratory Function of the Blood, 2nd ed. (Cambridge [Eng.] University Press, 1925), Vol. I. Haldane never gave up his belief in the existence and physiological importance of oxygen secretion in the lungs (see, for instance, Respiration, 2nd ed., p. 293), but few, if any physiologists today share his belief. The question, however is not necessarily closed. The whole controversy deserves an article to itself; we cannot pursue the matter further here.

  54. See n. 39.

  55. See Zuntz, n. 19, p. 81.

  56. See n. 47, esp. pp. 106–107 of this review.

  57. B.Werigo, “Zur Frage über die Wirkung des Sauerstoffs auf die Kohlensäureausscheidung in den Lungen,” Pflügers Arch. ges. Physiol., 51 (1892), 321–361.

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  58. Halberstadt's results were not published separately but were discussed by Bohr in his review (n. 47, p. 207).

  59. L. J.Henderson, Blood: A Study in General Physiology (New Haven: Yale University Press, 1928. pp. 80–81.

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  60. See also J.Parascandola, “Organismic and Holistic concepts in the Thought of L. J. Henderson,” J. Hist. Biol., 4 (1971), 63–113. A discussion of this point, with a quotation from Henderson's unpublished “Memories,” occurs on pp. 88–90.

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  61. See n. 8.

  62. See n. 9.

  63. For a biographical study of Haldane, see C. G.Douglas, “John Scott Haldane, 1860–1936,” Obituary Notices of Fellows of the Royal Society, 2 (1936), 115–139; also J. B. S. Haldane, “The Scientific work of J. S. Haldane,” Nature, 187 (1960), 102–105. The latter article gives references to a number of Haldane's most important papers. See also Garland E. Allen, “J. S. Haldane: The Development of the Idea of Control Mechanisms in Respiration,” J. Hist. Med., 22 (1967), 392–412. Allen deals with what was probably Haldane's most important single contribution to physiology; the discussion in the present paper treats of other, though closely related, aspects of this work.

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  64. J. S.Haldane, “The Action of Carbonic Oxide on Man,” J. Physiol., 18 (1895), 430–462.

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  65. See Douglas, n. 63. p. 119.

  66. J. S.Haldane, “A Contribution to the Chemistry of Haemoglobin and its Immediate Derivatives,” J. Physiol., 22 (1898), 298–306; “The Ferricyanide Method of Determining the Oxygen Capacity of Blood,” ibid., 25 (1900), 295–302; J. Barcroft and J. S. Haldane, “A Method of Estimating Oxygen and Carbonic Acid in Small Quantities of Blood,” ibid., 28 (1902), 232–240.

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  67. Published by Cambridge University Press, 1914. The second edition appeared in two volumes from the same publisher: vol. I, Lessons from High Altitudes (1925), and vol. II, Haemoglobin (1928). This edition, of course, contains material of great importance that was not in the first edition and is written with Barcroft's characteristic vividness and charm, but it does not have quite the zest and vitality of the first edition.

  68. Barcroft's personal influence was certainly greater than the record of his distinguished scientific achievement alone would convey. One may appreciate this by reading the personal recollections and tributes of his colleagues, E. D. Adrian, Sir Henry Dale, A. S. Krogh, C. G. Douglas, A. V. Hill, R. A. Peters, G. S. Adair, and F. J. W. Roughton, in Hemoglobin: A Symposium based on a Conference held at Cambridge in June 1948 in Memory of Sir Joseph Barcroft,” ed. F. J. W. Roughton and J. C. Kendrew (London, 1949). The biography by K. J. Franklin, Joseph Barcroft, 1872–1947 (Oxford, 1953), portrays the man and his career in great detail and gives an essentially complete bibliography of his published work. For one aspect of Barcroft's work and thought, which has some close relations with our discussion here, see F. L. Holmes, “Joseph Barcroft and the Fixity of the Internal Environment,” J. Hist. Biol., 2 (1969), 89–122.

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  69. Barcroft, Respiratory Function of the Blood, 1st ed., pp. 42–47.

  70. G. S.Adair, “The Hemoglobin System,” a series of six papers, some written in collaboration with A. V. Bock and H. Field Jr., J. Biol. Chem., 63 (1925), 493–546.

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  71. See Hemoglobin, p. 30 (above, n. 68). For the original papers, see J.Barcroft and M.Camis, “The Dissociation Curve of Blood,” J. Physiol., 39 (1909), 118–142; J. Barcroft and Ff. Roberts, “The Dissociation Curve of Hemoglobin,” ibid., 39 (1909), 143–148.

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  72. J.Barcroft and L.Orbeli, “The Influence of Lactic Acid upon the Dissociation Curve of Blood,” J. Physiol., 41 (1910), 355–367; J. Barcroft, “The Effect of Altitude on the Dissociation Curve of Blood,” ibid., 42 (1911), 44–63.

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  73. L. J.Henderson, “Concerning the Relation between the Strength of Acids and their Capacity to Preserve Neutrality,” Am. J. Physiol., 21 (1908), 173–179; “The Theory of Neutrality Regulation in the Animal Organism,” ibid., 21 (1908), 427–448; S. P. L. Sørensen “Enzymstudien: II Mitteilung, Ueber die Messung und die Bedeutung der Wasserstoffionen Konzentration, bei Enzymatischen Prozessen,” Biochem. Z., 21 (1909), 131–304. See also J. Parascandola, “L. J. Henderson and the Theory of Buffer Action,” Medizinhistorisches Journal, 7 (1972), 9–21.

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  74. See n. 22.

  75. WolfgangOstwald, “Ueber die Natur der Bindung der Gase im Blut und in seinen Bestandteilen,” Kolloidzeitschrift, 2 (1907–08), 264–272, 294–301; W. Manchot, “Untersuchungen über die Sauerstoffbindung im Blute,” Liebigs Ann. Chem., 370 (1909), 241–285. Wolfgang Ostwald should not be confused with his father, Wilhelm Ostwald, the well-known physical chemist and founder of the Zeitschrift für Physikalische Chemie. I have discussed elsewhere (above, n. 3) the often confusing influence of the “colloidal” school on the development of protein chemistry.

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  76. R. A.Peters, “Chemical Nature of Specific Oxygen Capacity of Hemoglobin,” J. Physiol., 44 (1912), 131–149. Barcroft, in his Respiratory Function of the Blood (1914), gives an interesting description of the progress of Peters's work, as seen by himself and by others in the laboratory.

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  77. W. M.Bayliss, Principles of General Physiology, 3rd ed. (London: Longmans Greene, 1920), pp. 618–625. The remark quoted is on p. 625.

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  78. A. V.Hill, “Bayliss and Starling and the Happy Fellowship of Physiologists: The Third Bayliss-Starling Memorial Lecture,” J. Physiol., 240 (1969), 1–13. See esp. p. 3. This article includes an interesting set of photographs of eminent British physiologists and biochemists.

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  81. J. S. Haldane, Respiration, 1st ed. (1922), p. 72.

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  86. G. Hüfner and E. Gansser, “Ueber das Molekulargewicht des Oxyhämoglobins,” Arch Physiol., Anat. (1907), 209–216.

  87. In another article (n. 3) I have discussed in more detail the intellectual resistance to the concept of definite macromolecules and the gradual acceptance of this concept as the evidence for it accumulated, especially from about 1925 on.

  88. H. E.Roaf, “The Relation of Proteins to Crystalloids. I.: The Osmotic Pressure of Hemoglobin and the Laking of Red Blood Corpuscles,” Q. J. exp. Physiol., 3 (1910), 75–96.

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  89. A. V.Hill, “The Possible Effects of the Aggregation of the Molecules of Hemoglobin on its Dissociation Curve,” J. Physiol., 40 (1910), iv-vii.

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  90. Ibid.

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  116. In his unpublished “Memories,” however, Henderson claimed that he had finally realized the necessary character of such a relation, shortly before the paper of Christiansen, Douglas, and Haldane appeared; so this statement need some qualification (see Parascandola, n. 60, p. 81).

  117. See n. 112, p. 258.

  118. At this time there was no way of determining the ratio of CO2 to H2CO3, in aqueous solutions, but since the two molecules must be present in a constant ratio, according to the law of mass action, they could be lumped together as a single component for analytical purposes. Within a few years it became possible, and important, to discriminate between CO2 and H2CO3, and to determine the rates of transformation of one into the other. We return to these questions in Part II. The fundamental assumption, that carbonic acid and bicarbonate accounted for all the CO2 in blood, had been denied by Bohr and several later workers—Parsons gives references to the controversy—but it seemed to most workers the best hypothesis available at the time. The later developments, which showed that this assumption was inadequate to account for all the facts, are also to be taken up in Part II.

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  123. Ibid.

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  127. Wyman, “Heme Proteins,” especially the two latter references in n. 126.

  128. See also n. 91.

  129. Note added in proof. I must call attention to the recent paper of Charles A. Culotta “Respiration and the Lavoisier Tradition: Theory and Modification, 1777–1850” Transactions of the American Philosophical Society, New Series 62, pt. 3 (1972), 41 pp. This provides important information, which I have not seen elsewhere, concerning this early period, including a detailed critical discussion of the work of Gustav Magnus in relation to his contemporaries. The fundamental paper by M. F. Perutz: “Stereochemistry of Cooperative Effects in Hemoglobin.” Nature 228 (1970), 726–738, based on his x-ray diffraction studies from 1937 to the present, appears now to offer a satisfactory basis for interpreting cooperative interactions and the Bohr effect in hemoglobin. Several subsequent papers from Perutz's laboratory, on mutant or chemically modified forms of hemoglobin, provide data in general accord with his proposals of 1970.

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    John T. Edsall

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Edsall, J.T. Blood and hemoglobin: The evolution of knowledge of functional adaptation in a biochemical system. Journal of the History of Biology 5, 205–257 (1972). https://doi.org/10.1007/BF00346659

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