The Development of Heparin in Toronto

Journal of the History of Medicine and Allied Sciences

Volumn 52, Issue 3, 1997, Pages 310-337

  Marcum, James A ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; HEPARIN;

ART; ARTICLE; CANADA; HISTORY; HUMAN;

ANTICOAGULANTS; HEPARIN; HISTORY, 20TH CENTURY; HUMANS; ONTARIO; PORTRAITS;

EID: 0031183349     PISSN: 00225045     EISSN: None     Source Type: Journal    
DOI: 10.1093/jhmas/52.3.310     Document Type: Article

References (162)

1. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
2. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
3. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
4. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
5. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
6. For accounts of the discovery of heparin, see Julius H. Comroe, Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park, Cal.: Von Gehr Press, 1977), pp. 13-14, 37, 90-92, 122-123; Nathan P. Couch, "About heparin, or . . . Whatever happened to Jay McLean?" J. Vasc. Surg., 1989, 10, 1-8; W. Bruce Fye, "Heparin: the contributions of William Henry Howell," Circulation, 1984, 69, 1198-1203; A. McGehee Harvey, "Fountainhead of American physiology: H. Newell Martin and his pupil, William Henry Howell," Johns Hopkins Med. J., 1975, 136, 38-46; Louis B. Jaques, "Addendum: the discovery of heparin," Semin. Thromb. Hemost., 1978, 4, 350-353; James A. Marcum, "William Henry Howell and Jay McLean: the experimental context for the discovery of heparin," Perspect. Biol. Med., 1990, 33, 214-230.
7. J. McLean, "The thromboplastic action of cephalin," Am. J. Physiol., 1916, 41, 250-257. For McLean's personal account on the discovery of heparin, see J. McLean, "The discovery of heparin," Circulation, 1959, 19, 75-78. For an assessment of McLean's contribution to the discovery of heparin, see "Jay McLean (1890-1957): discoverer of heparin" (editorial), J. Am. Med. Assoc., 1967, 201, 770; Conrad R. Lam, "The strange story of Jay McLean, the discoverer of heparin," Henry Ford Hosp. J., 1985, 33, 18-23.
8. J. McLean, "The thromboplastic action of cephalin," Am. J. Physiol., 1916, 41, 250-257. For McLean's personal account on the discovery of heparin, see J. McLean, "The discovery of heparin," Circulation, 1959, 19, 75-78. For an assessment of McLean's contribution to the discovery of heparin, see "Jay McLean (1890-1957): discoverer of heparin" (editorial), J. Am. Med. Assoc., 1967, 201, 770; Conrad R. Lam, "The strange story of Jay McLean, the discoverer of heparin," Henry Ford Hosp. J., 1985, 33, 18-23.
9. J. McLean, "The thromboplastic action of cephalin," Am. J. Physiol., 1916, 41, 250-257. For McLean's personal account on the discovery of heparin, see J. McLean, "The discovery of heparin," Circulation, 1959, 19, 75-78. For an assessment of McLean's contribution to the discovery of heparin, see "Jay McLean (1890-1957): discoverer of heparin" (editorial), J. Am. Med. Assoc., 1967, 201, 770; Conrad R. Lam, "The strange story of Jay McLean, the discoverer of heparin," Henry Ford Hosp. J., 1985, 33, 18-23.
10. J. McLean, "The thromboplastic action of cephalin," Am. J. Physiol., 1916, 41, 250-257. For McLean's personal account on the discovery of heparin, see J. McLean, "The discovery of heparin," Circulation, 1959, 19, 75-78. For an assessment of McLean's contribution to the discovery of heparin, see "Jay McLean (1890-1957): discoverer of heparin" (editorial), J. Am. Med. Assoc., 1967, 201, 770; Conrad R. Lam, "The strange story of Jay McLean, the discoverer of heparin," Henry Ford Hosp. J., 1985, 33, 18-23.
11. W.H. Howell and E. Holt, "Two new factors in blood coagulation - heparin and proantithrombin." Am. J. Physiol., 1918, 47, 328-341. Howell and Holt listed six factors involved in fibrin deposition. Today there are more than a dozen factors recognized as part of the blood clotting scheme. For a review of the development of blood coagulation research during the twentieth century, see Oscar D. Ratnoff, "Why do people bleed?" in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York, McGraw-Hill, 1980), pp. 601-657.
12. W.H. Howell and E. Holt, "Two new factors in blood coagulation - heparin and proantithrombin." Am. J. Physiol., 1918, 47, 328-341. Howell and Holt listed six factors involved in fibrin deposition. Today there are more than a dozen factors recognized as part of the blood clotting scheme. For a review of the development of blood coagulation research during the twentieth century, see Oscar D. Ratnoff, "Why do people bleed?" in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York, McGraw-Hill, 1980), pp. 601-657.
13. W.H. Howell, "Heparin, an anticoagulant," Am. J. Physiol., 1922, 63, 434-435; W.H. Howell, "The purification of heparin and its chemical and physiological reactions," Bull. Johns Hopkins Hosp., 1928, 42, 199-206.
14. W.H. Howell, "Heparin, an anticoagulant," Am. J. Physiol., 1922, 63, 434-435; W.H. Howell, "The purification of heparin and its chemical and physiological reactions," Bull. Johns Hopkins Hosp., 1928, 42, 199-206.
15. Joseph Erlanger, "William Henry Howell, 1860-1945," Biogr. Mem. Natl. Acad. Sci. U.S.A., 1950, 26, 153-180.
16. At the turn of the century researchers recognized the presence of an inhibitor to blood clotting, called antithrombin, in mammalian blood but were unable to isolate it. Paul Morawitz, The Chemistry of Blood Coagulation, trans. Robert Hartman and Paul F. Guenther (Springfield, Ill.: Charles Thomas, 1905/1958).
17. Louis K. Diamond, "A history of blood transfusion," in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York, McGraw-Hill, 1980), pp. 659-688. Other anticoagulants were also used during the early part of the twentieth century. For example Oswald H. Robertson, one of the originators of the blood bank, promoted the use of citrate, in a glucose solution, for indirect blood transfusion. Ibid.
18. Louis K. Diamond, "A history of blood transfusion," in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York, McGraw-Hill, 1980), pp. 659-688. Other anticoagulants were also used during the early part of the twentieth century. For example Oswald H. Robertson, one of the originators of the blood bank, promoted the use of citrate, in a glucose solution, for indirect blood transfusion. Ibid.
19. In the early part of the twentieth century, an effective blood anticoagulant would have facilitated the development of surgical procedures for the reattachment of blood vessels. For example, the work of Alexis Carrel and Charles C. Guthrie, among others, on the anastomosis of blood vessels would have benefited from a usable blood anticoagulant. W. Sterling Edwards and Peter D. Edwards, Alexis Carrel, Visionary Surgeon (Springfield, Ill.: Charles C. Thomas, 1974), pp. 8-13 and 25-37, Steven G. Friedman, A History of Vascular Surgery (Mount Kisco, N.Y.: Futura, 1989), p. 97.
20. In the early part of the twentieth century, an effective blood anticoagulant would have facilitated the development of surgical procedures for the reattachment of blood vessels. For example, the work of Alexis Carrel and Charles C. Guthrie, among others, on the anastomosis of blood vessels would have benefited from a usable blood anticoagulant. W. Sterling Edwards and Peter D. Edwards, Alexis Carrel, Visionary Surgeon (Springfield, Ill.: Charles C. Thomas, 1974), pp. 8-13 and 25-37, Steven G. Friedman, A History of Vascular Surgery (Mount Kisco, N.Y.: Futura, 1989), p. 97.
21. Howell "feared at times that H. W. & D. [Hynson, Wescott and Dunning] would give up [heparin's] production as they always claimed that it was a losing proposition to them." W.H. Howell to C.H. Best, 14 November 1931, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
22. For accounts on the development of heparin, see Ronald J. Baird, "Presidential address: 'Give us the tools . . . ' the story of heparin - as told by the sketches from the lives of William Howell, Jay McLean, Charles Best, and Gordon Murray," J. Vasc. Surg., 1990, 11, 4-18; W.G. Bigelow, Mysterious Heparin: The Key to Open Heart Surgery (Toronto: McGraw-Hill Ryerson, 1990); Lars Erik Boettiger, "The heparin story: in search of the early history of heparin," Acta Med. Scand., 1987, 222, 195-200; Lennart Roden and David S. Feingold, "A vintage year for Jorpes, Crafoord, and heparin," Trends Biochem. Sci., 1985, October, 407-409.
23. For accounts on the development of heparin, see Ronald J. Baird, "Presidential address: 'Give us the tools . . . ' the story of heparin - as told by the sketches from the lives of William Howell, Jay McLean, Charles Best, and Gordon Murray," J. Vasc. Surg., 1990, 11, 4-18; W.G. Bigelow, Mysterious Heparin: The Key to Open Heart Surgery (Toronto: McGraw-Hill Ryerson, 1990); Lars Erik Boettiger, "The heparin story: in search of the early history of heparin," Acta Med. Scand., 1987, 222, 195-200; Lennart Roden and David S. Feingold, "A vintage year for Jorpes, Crafoord, and heparin," Trends Biochem. Sci., 1985, October, 407-409.
24. For accounts on the development of heparin, see Ronald J. Baird, "Presidential address: 'Give us the tools . . . ' the story of heparin - as told by the sketches from the lives of William Howell, Jay McLean, Charles Best, and Gordon Murray," J. Vasc. Surg., 1990, 11, 4-18; W.G. Bigelow, Mysterious Heparin: The Key to Open Heart Surgery (Toronto: McGraw-Hill Ryerson, 1990); Lars Erik Boettiger, "The heparin story: in search of the early history of heparin," Acta Med. Scand., 1987, 222, 195-200; Lennart Roden and David S. Feingold, "A vintage year for Jorpes, Crafoord, and heparin," Trends Biochem. Sci., 1985, October, 407-409.
25. For accounts on the development of heparin, see Ronald J. Baird, "Presidential address: 'Give us the tools . . . ' the story of heparin - as told by the sketches from the lives of William Howell, Jay McLean, Charles Best, and Gordon Murray," J. Vasc. Surg., 1990, 11, 4-18; W.G. Bigelow, Mysterious Heparin: The Key to Open Heart Surgery (Toronto: McGraw-Hill Ryerson, 1990); Lars Erik Boettiger, "The heparin story: in search of the early history of heparin," Acta Med. Scand., 1987, 222, 195-200; Lennart Roden and David S. Feingold, "A vintage year for Jorpes, Crafoord, and heparin," Trends Biochem. Sci., 1985, October, 407-409.
26. "In the Connaught Laboratories," reminisced Best in the late 1950s, "I had been intimately concerned with the preparation of insulin and liver extract for administration to human patients and I visualized a similar advance in the heparin field." C.H. Best, "Preparation of heparin and its use in the first clinical cases," Circulation, 1959, 19, 79-86, p. 81. Louis Jaques, a doctoral student working with the Toronto heparin team, also claimed that "the success with heparin in Toronto was a logical outcome of the development of insulin." Bigelow, (n. 10) Mysterious Heparin, p. 39.
27. "In the Connaught Laboratories," reminisced Best in the late 1950s, "I had been intimately concerned with the preparation of insulin and liver extract for administration to human patients and I visualized a similar advance in the heparin field." C.H. Best, "Preparation of heparin and its use in the first clinical cases," Circulation, 1959, 19, 79-86, p. 81. Louis Jaques, a doctoral student working with the Toronto heparin team, also claimed that "the success with heparin in Toronto was a logical outcome of the development of insulin." Bigelow, (n. 10) Mysterious Heparin, p. 39.
28. C.H. Best, "Heparin and thrombosis," Can. Med. Assoc. J., 1938, 38, 59-60, p. 59.
29. Frank Young and C.N. Hales, "Charles Herbert Best, 1899-1978" Biogr. Mem. R. Soc. Lond., 1982, 28, 1-25.
30. W.S. Feldberg, "Henry Hallett Dale, 1875-1968," Biogr. Mem. Roy. Soc. Lond., 1970, 16, 77-173.
31. Ibid., p. 124.
32. Dale wrote later that he and Best enjoyed "a scientific and closely personal friendship over now more than forty years." H. H. Dale, "Forward," in Selected Papers of Charles H. Best (Toronto: University of Toronto Press, 1963), pp. vii-ix, p. ix.
33. Best, (n. 11), p. 81.
34. Ibid. In 1929 McHenry received his doctorate from the University of Toronto for his work on histamine, and he later chaired the Department of Nutrition in the School of Hygiene at the University of Toronto. D.A. Scott, "Earl Willard McHenry, 1899-1961," Proc. R. Soc. Can., 1962, 56, 219-224. In 1932 Glaister received her medical degree from the University of Toronto and practiced medicine in Kitchener, Ontario. J.K.W. Ferguson, 1 July 1996, letter to the author. J.K.W. Ferguson was director of Connaught from 1955-72. Roger J.F. Baskett, "James Kenneth Wallace Ferguson: a life in Canadian medical research," Ann. R. Coll. Phys. Surg. Can., 1996, 29, 105-108.
35. Ibid. In 1929 McHenry received his doctorate from the University of Toronto for his work on histamine, and he later chaired the Department of Nutrition in the School of Hygiene at the University of Toronto. D.A. Scott, "Earl Willard McHenry, 1899-1961," Proc. R. Soc. Can., 1962, 56, 219-224. In 1932 Glaister received her medical degree from the University of Toronto and practiced medicine in Kitchener, Ontario. J.K.W. Ferguson, 1 July 1996, letter to the author. J.K.W. Ferguson was director of Connaught from 1955-72. Roger J.F. Baskett, "James Kenneth Wallace Ferguson: a life in Canadian medical research," Ann. R. Coll. Phys. Surg. Can., 1996, 29, 105-108.
36. Paul A. Bator, Within the Reach of Everyone: A History of the University of Toronto School of Hygiene and Connaught Laboratories Limited, 2 vols. (Ottawa: Canadian Public Health Association, 1995), 2, 87.
37. J.K.W. Ferguson, 2 January 1996, interview with the author; Ferguson, (n. 18).
38. A.F. Charles, "Investigations on insulin and the preparation of heparin" (Ph.D. diss., University of Toronto, 1932).
39. Robert D. Defries, The First Forty Years 1914-1953: Connaught Medical Research Laboratories, University of Toronto (Toronto: University of Toronto Press, 1968).
40. Ibid., p. 73.
41. C.H. Best and A.M. Fisher, "David Alymer Scott, 1892-1971," Biogr. Mem. R. Soc. Can., 1972, 18, 511-524, p. 515.
42. Christian A. Herter of Columbia University founded the journal in 1905. Russel H. Chittenden, The Development of Physiological Chemistry in the United States (New York: Chemical Catalog Co., 1930), p. 178.
43. A.F. Charles and D.A. Scott, "Studies on heparin. I. The preparation of heparin," J. Biol. Chem., 1933, 102, 425-429.
44. Albert M. Fisher, who joined the Toronto insulin team in 1932, commented that the "odour in the Connaught Laboratories was so awful that they had to move their [heparin] research team to the Connaught Farm, which did not add to the profile of the project One of the team experienced a general evacuation of all the seats near him while he was watching a movie." Bigelow, (n. 10) Mysterious Heparin, p. 40.
45. According to Howell's original assay, one unit of heparin prevented one milliliter of cold cat's blood from coagulating within twenty-four hours.
46. A.F. Charles and D.A. Scott, "Studies on heparin. II. Heparin in various tissues," J. Biol. Chem., 1933, 102, 431-435.
47. Fisher commented on the impact of the pet food industry on the heparin project: "No sooner had Charles and Scott obtained an active extract from inexpensive bulk beef liver than liver became a popular pet food, which drove the price out of range." Bigelow, (n. 10) Mysterious Heparin, p. 39.
48. W.H. Howell, "The purification of heparin and its presence in blood," Am. J. Physiol., 1925, 17, 553-562. Howell argued that the amount of heparin in blood was relatively small in comparison to other tissues because of its potency.
49. Charles and Scott, (n. 29), p. 434. Kenneth W. Thompson, Medical Director of Roche-Organon, Inc., inquired in 1947 whether Best considered renaming heparin, given that it was originally named by Howell because of its isolation from the liver and yet heparin is not specific to that organ. Best responded that he had but: "Professor Howell suggested the name and it is now well-established. I feel, therefore, that it would be unwise to attempt a change." C.H. Best to K.W. Thompson, 9 July 1947, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
50. D.A. Scott and A.F. Charles, "Studies on heparin. III. The purification of heparin," J. Biol. Chem., 933, 102, 437-448. Best later clarified the use of the term "pure" by the Toronto heparin team. "The word pure is used here," he explained, "to indicate a uniform preparation, of standard potency, and free from toxic components rather than in the true chemical sense." Best, (n. 11), p. 83.
51. Lloyd's reagent is aluminum silicate, discovered by and named after John Uri Lloyd. J.U. Lloyd, "Discovery of the alkaloidal affinities of hydrous aluminum silicate," J. Am. Pharmacol. Assoc., 1916, 5, 381-495. Roy Bird Cook, "John Uri Lloyd: pharmacist, philosopher, author, man," J. Am. Pharmacol. Assoc. Prac. Pharm. Ed., 1949, 10, 538-544.
52. Lloyd's reagent is aluminum silicate, discovered by and named after John Uri Lloyd. J.U. Lloyd, "Discovery of the alkaloidal affinities of hydrous aluminum silicate," J. Am. Pharmacol. Assoc., 1916, 5, 381-495. Roy Bird Cook, "John Uri Lloyd: pharmacist, philosopher, author, man," J. Am. Pharmacol. Assoc. Prac. Pharm. Ed., 1949, 10, 538-544.
53. Later Scott and Charles discovered that the assay they performed in the early 1930s was not conducted strictly according to Howell's protocol. The temperature at which they performed the assay was lower than the temperature at which Howell conducted it. This lower temperature accounted for the inflated specific activity reported by Scott and Charles in 1933. Ferguson, (n. 18).
54. Scott and Charles, (n. 33), p. 443.
55. Ibid., p. 447.
56. In 1931, Best sought Howell's approval to market and sell heparin: "Would you have any objection if this material should be sold by the Connaught Laboratories?" Howell responded with no objections. C.H. Best to W.H. Howell, 10 November 1931, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
57. Cornish gained public notoriety for his resuscitation experiments. He also appeared in a "B movie" based on his experiments; but the medical establishment vigorously protested the film, for fear of the response from antivivisectionists. S.E. Lederer, "Laboratory life on the silver screen: animal experimentation and the film industry, 1930-1940," unpublished paper presented at the History of Science Society, Santa Fe, New Mexico, November 1993.
58. R.E. Cornish to Connaught Laboratories, 29 August 1934, Best Papers, Thomas Fisher Rare Book Library, University of Toronto, Ontario.
59. A.F. Charles and D.A. Scott, "Studies on heparin. IV. Observations on the chemistry of heparin," Biochem. J., 1936, 30, 1927-1933.
60. In agreement with Erik Jorpes' 1935 results (see below), Charles and Scott also detected the presence of sulfates in their heparin preparations.
61. Bigelow, (n. 10) Mysterious Heparin, pp. 50-55; Magareta Blombaeck, "Erik Jorpes, 1894-1973," Thrombos. Diathes. Haemorrh., 1974, 33, 11-16.
62. Bigelow, (n. 10) Mysterious Heparin, pp. 50-55; Magareta Blombaeck, "Erik Jorpes, 1894-1973," Thrombos. Diathes. Haemorrh., 1974, 33, 11-16.
63. J.E. Jorpes, "Heparin: a mucopolysaccharide and an active antithrombotic drug," Circulation, 1959, 19, 87-91, p. 89.
64. Apparently Jorpes did not formally thank Best for his hospitality in 1929 until 1935: "I . . . would like to use this opportunity to thank you for all the hospitality shown to me and to Mr. Bjurling during our visit in Toronto in 1929. We have greatly benefited [from] your experience in the manufacture of insulin." E. Jorpes to C.H. Best, 8 May 1935, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
65. Besides the work conducted in Toronto and Stockholm, Albert Fischer and co-workers from the Biological Institute of the Carlsberg Foundation in Copenhagen also isolated heparin in the early 1930s and examined its chemical composition and structure. A. Fischer, "Studies on coagulation of the blood," Jpn. J. Exp. Med., 1935, 13, 223-242.
66. In his 1939 monograph on heparin, Jorpes claimed that the "secret" to its chemical nature and action was in the ash. J.E. Jorpes, Heparin: Its Chemistry, Physiology and Application in Medicine (London, Oxford University Press, 1939), pp. 10-12.
67. E. Jorpes, "The chemistry of heparin," Biochem. J., 1935, 29, 1817-1830.
68. The reason for Jorpes' insistence upon sulfate as the important element was his observation that heparin's anticoagulant activity was directly dependent on its sulfate content (see below).
69. Levene was a pioneer in the field of hexosamines and mucoproteins, as well as nucleic acids. D.D. Van Slyke and W.A. Jacobs, "Phoebus Aaron Theodor Levene, 1869-1940," Biogr. Mem. Natl. Acad. Sci. U.S.A., 1944, 23, 75-126. Previously Levene and Frederick B. La Forge demonstrated that chondroitin sulfuric acid from nasal septa contained galactosamine and glucuronic acid. P.A. Levene, Hexosamines and Mucoproteins (London: Longmans, Green, 1925).
70. Levene was a pioneer in the field of hexosamines and mucoproteins, as well as nucleic acids. D.D. Van Slyke and W.A. Jacobs, "Phoebus Aaron Theodor Levene, 1869-1940," Biogr. Mem. Natl. Acad. Sci. U.S.A., 1944, 23, 75-126. Previously Levene and Frederick B. La Forge demonstrated that chondroitin sulfuric acid from nasal septa contained galactosamine and glucuronic acid. P.A. Levene, Hexosamines and Mucoproteins (London: Longmans, Green, 1925).
71. E. Jorpes, "Eine Methode zur Darstellung der Chondroitinschwefelsaeure," Biochem. Zeitschr., 1929, 204, 354-360.
72. In 1934 Bergstroem began his research career with Jorpes. In 1982 he was awarded a Nobel Prize for his work on prostaglandins. Annette O'Connor, "Sune K.D. Bergstroem, 1982," in Frank N. Magill, ed., The Nobel Prize Winners: Physiology and Medicine (Pasadena, Cal.: Salem Press, 1991), pp. 1403-1409.
73. E. Jorpes and S. Bergstroem, "Heparin: a mucoitin polysulfuric acid," J. Biol. Chem., 1937, 118, 447-457.
74. P.A. Levene and J. Lopez-Suarez, "The conjugated sulfuric acid of the mucin of pig's stomach (mucoitin sulfuric acid)," J. Biol. Chem., 1916, 25, 511-516.
75. P.A. Levene to C.H. Best, 27 March 1939, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
76. C.H. Best to P.A. Levene, 31 March 1939, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
77. L.B. Jaques, 9 April 1996, personal communication.
78. A.R. Todd, A Time to Remember (Cambridge: Cambridge University Press, 1983).
79. A.R. Todd, "Obituary, Sir Robert Robinson," Nature, 1975, 253, 761.
80. A.F. Charles to C.H. Best, 9 March 1939, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
81. A.F. Charles and A.R. Todd, "Observations on the structure of the barium salt of heparin," Biochem. J., 1940, 34, 112-118.
82. Ibid., p. 113.
83. E. Jorpes and S. Bergstroem, "On the relationship between the sulphur content and the anticoagulant activity of heparin preparations," Biochem. J., 1939, 33, 47-52, p. 51.
84. In 1939, Jaques prepared a large quantity of heparin at Connaught Laboratories, based on the isolation protocol of Charles and Scott, and deposited the material in London as an international standard. Ferguson, (n. 18). See also Best, (n. 11), p. 82.
85. Jorpes and Bergstroem, (n. 63), p. 51.
86. Charles and Todd, (n. 61), p. 116.
87. Charles and Best, (n. 60).
88. A.F. Charles to C.H. Best, 30 June 1939, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
89. L.B. Jaques to J.K.W. Ferguson, 19 September 1987, photocopy of letter given to author.
90. D.A. Scott, A.F. Charles, and A.M. Fisher, "New crystalline compounds of heparin," Trans. R. Soc. Can. 1942, 36, 49-53.
91. D.A. Scott and A.M. Fisher, "New crystalline compounds of insulin," Trans. R. Soc. Can. 1942, 36, 45-47.
92. R.L. MacMillan and A.F. Charles, "Heparin and anticoagulant therapy," Ont. Med. Rev., 1953, 20, 608-609.
93. A.F. Charles, "Heparin," Contox, 1971, 38, 1-2.
94. E. Jorpes, "On the chemistry of heparin," Biochem. J., 1942, 36, 203-213.
95. Ibid., p. 212.
96. L.B. Jaques to J.K.W. Ferguson, 5 May 1986, photocopy of letter given to author.
97. Best, (n.11), p. 82.
98. For an account on the Toronto General Hospital, see W.G. Crosbie, The Toronto General Hospital 1819-1965: A Chronicle (Toronto: Macmillan, 1975).
99. Robert I. Harris and Robert M. Janes, eds. Essays in Surgery Presented to Dr. W.E. Gallie (Toronto: University of Toronto Press, 1950), pp. ix-xxiv.
100. Ibid., p. ix.
101. C.H. Best, "Heparin in blood clotting and thrombosis," in Essays in Surgery, (n. 79), pp. 3-9, p. 3.
102. Gordon Murray, Medicine in the Making (Toronto: Ryerson Press, 1960) pp. 26-56.
103. Ibid., p. 73.
104. L.B. Jaques, "Reminiscences on completing twenty-five years of research in the blood coagulation field," Univ. Sask. Med. J., 1960, 3, 1-3.
105. Chute, who worked with Murray from 1933 to 1934, was a nursing student at the University of Toronto, L.B. Jaques, 9 February 1996, personal communication.
106. L.B. Jaques, "Heparin - a challenging enigma," J. Orthomole. Med., 1993, 8, 139-144, p. 139.
107. Murray, (n. 82) Medicine in the Making, p. 225.
108. D.W.G. Murray, L.B. Jaques, T.S. Perrett and C.H. Best, "Heparin and vascular occlusion," Can. Med. Assoc. J., 1936, 35, 621-622.
109. Earlier, Howell and C.H. McDonald injected heparin intravenously into dogs and reported that there was little effect upon the physiology of the blood or the animal. W.H. Howell and C.H. McDonald, "Note on the effect of repeated intravascular injections of heparin," Bull. Johns Hopkins Hosp., 1930, 46, 365-368. Edward C. Mason also reported no harmful effects from repeated injections of heparin into dogs, but found that it elicited toxic side effects in humans. E.C. Mason, "A note on the use of heparin in blood transfusion," J. Lab. Clin. Med., 1924, 10, 203-207.
110. Earlier, Howell and C.H. McDonald injected heparin intravenously into dogs and reported that there was little effect upon the physiology of the blood or the animal. W.H. Howell and C.H. McDonald, "Note on the effect of repeated intravascular injections of heparin," Bull. Johns Hopkins Hosp., 1930, 46, 365-368. Edward C. Mason also reported no harmful effects from repeated injections of heparin into dogs, but found that it elicited toxic side effects in humans. E.C. Mason, "A note on the use of heparin in blood transfusion," J. Lab. Clin. Med., 1924, 10, 203-207.
111. D.W.G. Murray, L.B. Jaques, T.S. Perrett, and C.H. Best, "Heparin and the thrombosis of veins following injury," Surgery, 1937, 2, 163-187.
112. Mechanical injury to the veins was accomplished by passing a silk thread through the lumen of the vessel and then crushing the tissue against the thread with a pair of artery forceps. Chemical injury to veins was produced by injecting sodium ricinoleate into the vessel and allowing the chemical to contact the intimai layer of the vessel for three minutes.
113. For Howell, in addition to being a chemical entity, heparin was a theoretical entity that he incorporated into an inhibitor theory of clotting. Marcum, (n. 1).
114. Angelo Baserga, "The hematologic work of Giulio Bizzozero," Sci. Med. Ital., 1958, 7, 43-63. Theodore H. Spaet, "Platelets: the blood dust," in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York: McGraw- Hill, 1980), pp. 549-571.
115. Angelo Baserga, "The hematologic work of Giulio Bizzozero," Sci. Med. Ital., 1958, 7, 43-63. Theodore H. Spaet, "Platelets: the blood dust," in Maxwell M. Wintrobe, ed., Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas (New York: McGraw-Hill, 1980), pp. 549-571.
116. Ratnoff, (n. 3), pp. 638-640.
117. J.W. Pickering, The Blood Plasma in Health and Disease (London: William Heinemann, 1928), p. 177.
118. L.G. Rowntree and T. Shionoya, "Studies in experimental extracorporeal thrombosis. I. A method for the direct observation of extracorporeal thrombus formation," J. Exp. Med., 1927, 46, 7-12; T. Shionoya, "Studies in experimental extracorporeal thrombosis. II. Thrombus formation in normal blood in the extracorporeal vascular loop," J. Exp. Med., 1927, 46, 13-18; T. Shionoya, "Studies in experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanism of thrombus formation," J. Exp. Med., 1927, 46, 19-28.
119. L.G. Rowntree and T. Shionoya, "Studies in experimental extracorporeal thrombosis. I. A method for the direct observation of extracorporeal thrombus formation," J. Exp. Med., 1927, 46, 7-12; T. Shionoya, "Studies in experimental extracorporeal thrombosis. II. Thrombus formation in normal blood in the extracorporeal vascular loop," J. Exp. Med., 1927, 46, 13-18; T. Shionoya, "Studies in experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanism of thrombus formation," J. Exp. Med., 1927, 46, 19-28.
120. L.G. Rowntree and T. Shionoya, "Studies in experimental extracorporeal thrombosis. I. A method for the direct observation of extracorporeal thrombus formation," J. Exp. Med., 1927, 46, 7-12; T. Shionoya, "Studies in experimental extracorporeal thrombosis. II. Thrombus formation in normal blood in the extracorporeal vascular loop," J. Exp. Med., 1927, 46, 13-18; T. Shionoya, "Studies in experimental extracorporeal thrombosis. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanism of thrombus formation," J. Exp. Med., 1927, 46, 19-28.
121. L.G. Rowntree, Amid Masters of Twentieth Century Medicine: A Panorama of Persons and Places (Springfield, Ill.: Charles Thomas, 1958), p. 115.
122. C.H. Best, C. Cowan and D.L. MacLean, "Heparin and the formation of white thrombi," Science, 1937, 85, 338-339.
123. Several years later, after Rowntree had moved to Philadelphia, investigators at the Mayo Clinic used heparin clinically. Hiram E. Essex and another colleague from the Mayo Clinic visited Toronto, to learn about its clinical application. Upon their return they treated a patient suffering from a pulmonary embolism with heparin. H.E. Essex to C.H. Best, 11 November 1937, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
124. C.H. Best, C. Cowan and D.L. MacLean, "Heparin and the formation of white thrombi," J. Physiol., 1938, 92, 20-31.
125. Gerald L. Geison, Michael Foster and the Cambridge School of Physiology: The Scientific Enterprise in Late Victorian Society (Princeton, N.J.: Princeton University Press, 1978), pp. 187-188.
126. Best often showed the film on thrombus formation at scientific meetings, prior to presentation of data on the antithrombotic action of heparin, as well as to his physiology classes at the medical school. The film generated several requests from other investigators for copies. See, e.g., A.J. D'Alessandro to C.H. Best, 4 March 1948, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
127. Best, Cowan, and MacLean, (n. 100), p. 28. According to the fibrin theory for platelet aggregation, fibrin entraps blood cells and platelets to form a thrombus.
128. D.W.G. Murray and C.H. Best, "Heparin and thrombosis: the present situation," J. Am. Med. Assoc., 1938, 110, 118-119.
129. C.H. Best to P.L. Straith, 1 June 1937, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
130. Gordon D.W. Murray, "Heparin in thrombosis and embolism," Br. J. Surg., 1940, 27, 567-598.
131. Murray, (n. 82) Medicine in the Making, p. 108.
132. H.S. Gasser to C.H. Best, 25 March 1940, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
133. C.H. Best, "Heparin and thrombosis," Harvey Lect., 1940-41, 36, 66-90.
134. M.M. Best, 29 November 1940, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
135. Murray, (n. 106), p. 582-83.
136. Ibid., p. 597.
137. According to Best, no single component of heparin was responsible for its anticoagulant activity; rather, the "activity is dependent upon all the groups in the molecule and their appropriate arrangement. The removal of sulphates, amino nitrogen or carboxyl groups causes almost complete disappearance of the anticoagulant activity." Best, (n. 109), p. 74.
138. For further discussion of heparin and peptone plasma, see J.A. Marcum, "The discovery of heparin revisited: the peptone connection," Perspect. Biol. Med., 1996, 39, 610-625.
139. Best, (n. 109), p. 68. According to Howell, heparin exhibited antithrombm activity by converting proantithrombin to antithrombin, which inhibited thrombin, and antiprothrombin activity by preventing the activation of prothrombin. Marcum, (n. 1).
140. L.B. Jaques, "Heparin in blood clotting and thrombosis" (Ph.D. diss., University of Toronto, 1941), p. 280.
141. Best, (n. 109), p. 83.
142. Ibid., p. 88.
143. Gordon Murray, Quest in Medicine (Toronto: Ryerson Press, 1963), pp. 1-28.
144. For example, Jaques investigated the effects of dicumarol and silicone on blood coagulation. He left Toronto in 1946 to head the physiology department at the University of Saskatchewan.
145. See Bigelow, (n. 10) Mysterious Heparin, pp. 93-101.
146. R.D. Rosenberg, K.A. Bauer, and J.A. Marcum, "The heparin-antithrombin system," Rev. Hematol., 1985, 2, 351-416.
147. L.B. Jaques to W.G. Bigelow, 17 October 1987, photocopy of letter given to author. Jaques stated elsewhere that "Dr. Best's contribution was in identifying the problem [heparin], making possible the financing, arranging for the facilities needed, and allowing each of a group of scientists to do his/her thing." L.B. Jaques to M. Bliss, 28 June 1986, photocopy of letter given to author.
148. J.K.W. Ferguson to L.B. Jaques, 7 August 1986, photocopy of letter given to author.
149. Jaques was responsible for the isolation of heparin at Connaught Laboratories during Charles' sabbatical year in England.
150. Best, (n. 11), p. 83.
151. Both Solandt and Thalhimer applied heparin to problems such as exchange transfusion and coronary thrombosis in experimental animals.
152. C.H. Best to E.C. Mason, 10 September 1938, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.
153. Jaques, (n. 116), p. 262.
154. MacKenzie became Murray's assistant, after Perrett left the team. J.K.W. Ferguson, 22 November 1996, personal communication.
155. Although only 29 years old when he was appointed a professor, Best became politically connected later in his career. For example, Jaques called him "a remarkable scientist - politician." L.B. Jaques to J.K.W. Ferguson, 27 December 1986, photocopy of letter given to the author.
156. Another indication of the tension between Best and Murray is Murray's version of heparin's development in Toronto. Murray did not recognize the contribution of Best to the heparin project. Rather he claimed that in his quest for an anticoagulant to use clinically: "There was none in the school or elsewhere [who] was thinking along these lines." Murray, (n. 82) Medicine in the Making, p. 80.
157. L.B. Jaques to J.K.W. Ferguson, 20 February 1986, photocopy of letter given to the author.
158. For example, Best often crossed his name off manuscripts presented to him by members of the heparin team, for work in which he did not participate personally. "Best did not allow his name on a paper," remembered Jaques, "unless he had either been engaged in the work at the lab bench or had written the paper himself with co-authors supplying the data." Bigelow, (n. 10) Mysterious Heparin, p. 75. Best has been criticized for his attempt to rewrite the insulin story. Michael Bliss, "Rewriting medical history: Charles Best and the Banting and Best myth," J. Hist. Med. Allied Sci., 1993, 48, 253-274. Although Best's portrayal of the heparin story was more accurate, part of the reason may be that heparin was not as significant to Best as insulin. According to Jaques, Best never "considered heparin more than a side issue for him. Certainly, [he] did not identify himself with it as he did with insulin." L.B. Jaques to M. Bliss, 28 June 1986, photocopy of letter given to author.
159. For example, Best often crossed his name off manuscripts presented to him by members of the heparin team, for work in which he did not participate personally. "Best did not allow his name on a paper," remembered Jaques, "unless he had either been engaged in the work at the lab bench or had written the paper himself with co-authors supplying the data." Bigelow, (n. 10) Mysterious Heparin, p. 75. Best has been criticized for his attempt to rewrite the insulin story. Michael Bliss, "Rewriting medical history: Charles Best and the Banting and Best myth," J. Hist. Med. Allied Sci., 1993, 48, 253-274. Although Best's portrayal of the heparin story was more accurate, part of the reason may be that heparin was not as significant to Best as insulin. According to Jaques, Best never "considered heparin more than a side issue for him. Certainly, [he] did not identify himself with it as he did with insulin." L.B. Jaques to M. Bliss, 28 June 1986, photocopy of letter given to author.
160. Best, (n. 11), p. 81. The School of Hygiene was another important institution within the University of Toronto system, for the development of heparin. Bator, (n. 19) Within the Reach of Everyone, 2, 11-30; Defries, (n. 22) The First Forty Years, pp. 80-90.
161. Best, (n. 11), p. 81. The School of Hygiene was another important institution within the University of Toronto system, for the development of heparin. Bator, (n. 19) Within the Reach of Everyone, 2, 11-30; Defries, (n. 22) The First Forty Years, pp. 80-90.
162. In a letter, Best corrected Jorpes's misidentification of Gallie for Murray: "It was Dr. Gallie and not Dr. Murray whom you saw in Stockholm last summer. Gallie was most favourably impressed with what he saw while he was with you." C.H. Best to E. Jorpes, 31 December 1937, Best Papers, Thomas Fisher Rare Book Library, University of Toronto.