Hostname: page-component-586b7cd67f-dlnhk Total loading time: 0 Render date: 2024-11-23T20:21:02.142Z Has data issue: false hasContentIssue false
  • English
  • Français

The Search for Synthetic Penicillin during World War II*

Published online by Cambridge University Press:  05 January 2009

John Patrick Swann
John Patrick Swann
Affiliation:
School of Pharmacy, University of Wisconsin, Madison, WI 53706.
Get access Rights & Permissions [Opens in a new window]

Extract

In the past thirty or forty years scientists, historians, and others have written many histories of the wonder drug, penicillin. However, almost all of these works fail to develop an important part of the history of penicillin: the attempt to synthesize the drug during the Second World War. Therefore, the purpose of this paper is to explore this largely unexamined episode in the history of science, and to answer some relevant questions. For example, why was there a need for synthetic penicillin? What organizational plans had to be made in order to accommodate this massive endeavor? What was the effect of the search for a synthesis on the natural production of this drug? And finally, did chemists ever devise a successful synthesis? Before attempting to answer these and other questions, a brief introduction to 1) the discovery and development of penicillin as a therapeutic agent, and 2) the general organization of wartime medical research in the United States and Great Britain, is necessary.

Type
Research Article
Information
The British Journal for the History of Science , Volume 16 , Issue 2 , July 1983 , pp. 154 - 190
Copyright
Copyright © British Society for the History of Science 1983

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1 The brief introduction to the development of penicillin as a chemotherapeutic agent is drawn largely from the following: Abraham, E. P. et al. , ‘Historical Introduction’, in Antibiotics, 2 vols., eds. Florey, H. W. et al. (London: Oxford University Press, 1949), vol. 2, pp. 631–71Google Scholar; Wilson, David, Penicillin in Perspective (London: Faber and Faber, 1976Google Scholar; published in the United States, 1976, by Alfred A. Knopf under the title, In search of Penicillin); and U. S. Federal Trade Commission, Economic Report on Antibiotics Manufacture (Washington, D. C.: Government Printing Office, 1958)Google Scholar, Appendix 2, ‘Discovery and Development of Penicillin’, pp. 302–54.

2 Pfizer was particularly fitted for penicillin production, since it had prior experience in deep fermentation. James N. Currie, of the Bureau of Animal Industry, had conducted investigations, c. 1917, on the nutritional and environmental conditions conducive to the production of citric acid by Aspergillus niger. Soon after his studies for the government were completed, Currie left to join Pfizer, and in 1923 this company began to produce citric acid by the deep fermentation of Aspergillus cultures, based on Currie's prior work. See Ward, George E., ‘Some Contributions of the U. S. Department of Agriculture to the Fermentation Industry’, Advan. Appl. Microbiol. 13 (1970): 364Google Scholar, and Chain, Ernst, ‘A Short History of the Penicillin Discovery From Fleming's Early Observations in 1929 to the Present Time’, in The History of Antibiotics: A Symposium, ed. Parascandola, John (Madison: American Institute of the History of Pharmacy, 1980), p. 24.Google Scholar

3 Green, F. H. K. and Covell, Gordon, Medical Research (London: Her Majesty's Stationery Office, 1953), p. 1Google Scholar, and Mellanby, Edward, ‘Medical Research in Wartime’, Brit. Med. J. (1943): 352.Google ScholarPubMed

4 Green, and Covell, , Medical Research, p. 5Google Scholar, and Mellanby, , ‘Medical Research’, 352–3.Google Scholar

5 Green, and Covell, , Medical Research, p. 2Google Scholar, and Mellanby, , ‘Medical Research’, 352Google Scholar. Green and Covell present a list of the investigators on the two penicillin committees on p. 372.

6 Stewart, Irvin, Organizing Scientific Research for War (Boston: Little, Brown, 1948)Google Scholar, reproduces this excutive order (no. 8807) on pp. 335–8. The above is taken from pp. 335–7 (Paragraphs 1; 2, sections b, f, and g; 3; and 4). (Stewart was the Executive Secretary of the CMR up to December, 1945.)

7 Ibid., p. 337 (Paragraph 8). The following were members of the Committee on Medical Research: Richards, Lewis H. Weed of the National Research Council, Vice-Chairman, A. R. Dochez, A. Baird Hastings, Brig. General James S. Simmons, Rear Admiral Harold W. Smith, and L. R. Thompson (R. E. Dyer replaced Thompson in November, 1942); See Andrus, E. C. et al. , eds., Advances in Military Medicine, 2 vols. (Boston: Little, Brown, 1949), vol. 1, p. ix.Google Scholar

8 Stewart, , Organizing Research, pp. 168–71Google Scholar, and Richards, A. N., Foreward to Advances in Military Medicine, 2 vols., eds. Andrus, E. C. et al. (Boston: Little, Brown, 1948), vol. 1, p. xlvi.Google Scholar

9 Elder, Albert L., ‘The Role of the Government in the Penicillin Program’, in The History of Penicillin Production, Chemical Engineering Progress Symposium Series No. 100, Vol. 66Google Scholar, ed. idem (New York: American Institute of Chemical Engineers, 1970), p. 4. Elder based this yield on the conversion of carbon in the growth medium into penicillin carbon.

10 ‘Penicillin Synthesis Is Not ‘Just Around Corner’—Adams’, Drug Trade News, 04 10, 1944 (clipping in KRF).Google Scholar

11 Coghill, Robert D., ‘Report of a trip to England during July and August, 1943’, c. 08 31, 1943, p. 1Google Scholar (NA, NRRL Papers, copy in KRF (p. 10 of this report is missing from the KRF copy)); Clarke, Hans T., Johnson, John R., and Robinson, Robert, eds., The Chemistry of Penicillin (Princeton: Princeton University Press, 1949), pp. v–viCrossRefGoogle Scholar; Perlman, D., ‘Some Mycological Aspects of Penicillin Production’, Bot. Rev. 16 (1950): 454CrossRefGoogle Scholar; Federal Trade Commission, Report on Antibiotics, p. 319Google Scholar; Wilson, , Penicillin, p. 222Google Scholar; Florey, H. W. and Abraham, E. P., ‘The Work on Penicillin at Oxford’, J. Hist. Med. 6 (1951): 312–3Google ScholarPubMed; and Chain, E., ‘The Chemistry of Penicillin’, Ann. Rev. Biochem. 17 (1948): 657.CrossRefGoogle ScholarPubMed

12 In October of 1942, the Ministry of Supply established the General Penicillin Committee, which did receive PEN reports. However, this Committee probably played a minor role in the coordination of research compared to the Penicillin Producer's Conference. See Clarke, , Johnson, , and Robinson, , Chemistry of Penicillin, p. v.Google Scholar

13 Green, and Covell, , Medical Research, pp. 318–19Google Scholar; Folkers, Karl, ‘Microorganisms in Organic Chemistry’, in Perspectives in Organic Chemistry, ed. Todd, Alexander (New York and London: Interscience Publishers, 1956), p. 407Google Scholar; and Clarke, , Johnson, , and Robinson, , Chemistry of Penicillin, pp. 1044–50.Google Scholar

14 Richards, A. N. to Drugs and Cosmetics Section, War Production Board, 06 4, 1943Google Scholar (copy in KRF; location of original unknown).

15 ‘War Production Board Controls All Penicillin’, Drug Trade News, 12 6, 1943Google Scholar (clipping in KRF).

16 This Committee, proposed by a member of the Chemicals Division of the WPB in August, 1941, consisted of representatives from companies producing penicillin, and followed ‘the general pattern of industry advisory committees appointed by WPB’. See Wilson, C. L., ‘Memorandum of Meeting for Discussion of Penicillin Program’, 09 10, 1943Google Scholar, quoted in Federal Trade Commission, Report on Antibiotics, pp. 329–30.Google Scholar

17 Richards, A. N. to Upjohn, L. N. (President, The Upjohn Company), 10 2, 1943Google Scholar (NA, Record Group (hereafter abbreviated as RG) 227, OSRD, CMR, General Correspondence, ‘Pfizer, 1941–1943’, copy in KRF).

18 Federal Trade Commission, Report on Antibiotics, p. 341.Google Scholar

19 Richards, to Upjohn, , 10 2, 1943.Google Scholar

20 ‘Ultimate Aims’ [Summary of a meeting between Bush, Richards, and Wilson on Aug. 21, 1943] (NA, RG 227, OSRD, Office of the Director, Special Subject File, ‘Penicillin’, 02–09, 1943, copy in KRF).Google Scholar

21 Clough, S. Dewitt to Richards, A. N., 10 15, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Abbott to Lilly’, copy in KRF).

22 Coghill, Robert D. to Richards, A. N., 05 22, 1943Google Scholar (NA, NRRL Papers, copy in KRF).

23 John Powers, Jr (Pfizer), Carl M. Anderson (Merck), and George Sibley (Squibb), to Merck, Palmer (Squibb), and Smith (Pfizer), copy of memorandum enclosed in George W. Merck (President, Merck and Co.) to A. N. Richards, Oct. 20, 1943 (NA, RG 227, OSRD, CMR, Contract File (alphabetical), Merck, copy in KRF). See also Lescohier, A. W. (President, Parke-Davis) to Richards, A. N., 10 9, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Parke Davis to Winthrop’, copy in KRF).

24 See Upjohn, L. N. to Richards, A. N., 10 8, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Parke Davis to Winthrop’, copy in KRF).

25 See, e.g., Wuest, H. M. to Richards, A. N., 11 4, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Abbott to Lilly’, copy in KRF).

26 On the OSRD security classifications, see Stewart, , Organizing Research, pp. 250–1.Google Scholar

27 See Bush, Vannevar to Clarke, Hans T., 11 17, 1943Google Scholar (NA, NRRL Papers, copy in KRF); Bush asked Clarke to be Chairman of this group. See also Richards, A. N., ‘Production of Penicillin in the United States (1941–1946)’, Nature 201 (1964): 445.CrossRefGoogle Scholar

28 Clarke, H. T., Adams, Roger, and Coghill, R. D. to the Director of the OSRD (memorandum), 11 19, 1943Google Scholar (NA, RG 227, OSRD, Office of the Director, Special Subject File, ‘Penicillin’, Oct.–Dec., 1943, copy in KRF).

The advisory committee was supposed to survey the chemical personnel and organizations, and make its recommendations based on this survey. However, it had only two days to do this—based on the dates of Bush's invitations to each committee member (see n. 27) and the committee's report to Bush (i.e., between Nov. 17 and Nov. 19). Two possibilities present themselves here. Perhaps the committee pooled its prior knowledge of manufacturers; at least two members did have some experience in industrial consultations. Or perhaps Richards was correct, in his letter to L. N. Upjohn of Oct. 2, 1943 (see n. 17), when he said a committee had recently been formed, consisting of Clarke, Adams, Coghill, and William M. Clark, to consider all matters relevant to the chemistry of penicillin. However, Bush's invitation to Clarke on Nov. 17 to serve as Chairman of a group consisting of he, Coghill, and Adams, seems to contradict Richards. Why would Bush invite Clarke to join a group and serve as its Chairman if Clarke had been part of this group for over a month? Also, Coghill replied to Bush on Nov. 22 (two days after the advisory committee's recommendations!) accepting his offer to join the same committee as Clarke. Again, inconsistencies seem to preclude a firm decision on the date this advisory group was established.

29 Clarke, , Adams, and Coghill, to Director of the OSRD, 11 19, 1943.Google Scholar

30 For example, see Klumpp, Theodore G. (President, Winthrop Chemical Company) to Richards, A. N., 10 20, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Parke Davis to Winthrop’, copy in KRF).

31 Ibid. See also Powers, , Anderson, , and Sibley, to Merck, , Palmer, , and Smith, , in Merck, to Richards, , 10 20, 1943Google Scholar; Clough, to Richards, , 10 15, 1943Google Scholar; and Lescohier, to Richards, , 10 9, 1943.Google Scholar

32 Klumpp, to Richards, , 10 20, 1943Google Scholar; Helfand, W. H. et al. , ‘Wartime Industrial Development of Penicillin in the United States’, in The History of Antibiotics: A Symposium, ed. Parascandola, John (Madison: American Institute of the History of Pharmacy, 1980), p. 40Google Scholar; Federal Trade Commission, Report on Antibiotics, p. 345Google Scholar; and Coghill, Robert D., ‘Penicillin: Science's Cinderella’, Chem. Eng. News 22 (1944): 589CrossRefGoogle Scholar. Helfand et al. claim that the manufacturers' liability under the anti-trust laws was not fully removed until June 21, 1944, even though these laws never really threatened the penicillin projects. The work by the Federal Trade Commission contends, however, that Nelson's signing of the ‘Proposal for Collaboration between Certain Companies and the Government’ on Dec. 7, 1943 (see p. 345 n. 46) in fact did remove any possibility of prosecutions under the anti-trust laws. Presumably, the argument here is that Chairman Nelson, by signing this agreement, made the WPB assume responsibility if anti-trust prosecutions were pursued.

33 The drug and chemical companies were Abbott, Lilly, Merck, Parke-Davis, Pfizer, Squibb, Upjohn and Winthrop, the last working jointly with Heyden. Cornell and Michigan were the two universities. See Federal Trade Commission, Report on Antibiotics, p. 346.Google Scholar

34 An untitled, unsigned copy of the contract between the government and Squibb (to be referred to as [Contract Between the U. S. Government and E. R. Squibb and Sons for Research on the Chemistry and Synthesis of Penicillin]) has been examined (NA, RG 227, OSRD, Office of the Director, Special Subject File, ‘Penicillin’, Oct.–Dec. 1943, copy in KRF). Although this particular contract applied only to Squibb, the other contracts were very similar. Cf. Stewart, , Organizing Research, pp. 339–46Google Scholar (Appendix 2). The contract itself states that, ‘… the Government intends to enter into agreements containing provisions substantially similar to those herein with other organizations which will conduct similar studies and investigations’ ([Contract Between the U. S. Government and E. R. Squibb and Sons for Research on the Chemistry and Synthesis of Penicillin], p. 1 (Preamble)).

35 [Contract Between the U. S. Government and E. R. Squibb and Sons for Research on the Chemistry and Synthesis of Penicillin], pp. 2–3 (Article 2, (a), (d), (e) and (f)).

36 Ibid., pp. 3 and 6 (Articles 2, (a); and 6).

37 These were very similar to the provisions which the drug and chemical companies suggested to Richards. For example, see Lilly, Eli (President, Eli Lilly and Co.) to Richards, A. N., 10 11, 1943Google Scholar (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin—Commercial—Abbott to Lilly’, copy in KRF); Powers, , Anderson, and Sibley, to Merck, , Palmer, , and Smith, , in Merck, to Richards, , 10 20, 1943Google Scholar; and Klumpp, to Richards, , 10 20, 1943.Google Scholar

38 Bush, Vannevar, [Transmittal Letter Accompanying Each Penicillin Synthesis Contract], pp. 2–3Google Scholar (NA, RG 227, OSRD, Office of the Director, Special Subject File, ‘Penicillin’, Oct.–Dec., 1943, copy in KRF). On the patent provisions, see [Contract Between the U. S. Government and E. R. Squibb and Sons for Research on the Chemistry and Synthesis of Penicillin], pp. 3–4 (Article 3, (a) and (b)).

39 Federal Trade Commission, Report on Antibiotics, pp. 320–1Google Scholar; Florey, and Abraham, , ‘Penicillin at Oxford’, 312–13Google Scholar; and Perlman, D., ‘Evolution of the Antibiotics Industry, 1940–1975’, ASM News 40 (1974): 910–1.Google Scholar

40 Green, and Covell, , Medical Research, p. 319.Google Scholar

41 Clarke, , Johnson, , and Robinson, , Chemistry of Penicillin, p. viGoogle Scholar, present a list of the organizations involved in the penicillin synthesis program.

42 Federal Trade Commission, Report on Antibiotics, pp. 54–5Google Scholar. Thirteen companies built plants at their own expense, four received full government assistance, and two firms both invested their own money and received, some federal support.

43 Elder, , ‘Government in Penicillin Program’, p. 4Google Scholar, and idem, ‘Penicillin’, Sci. Monthly 58 (1944): 409.Google Scholar

44 Federal Trade Commission, Report on Antibiotics, p. 53.Google Scholar

45 ‘Medical Societies: Biochemical Society’, Lancet 2 (1941): 762.Google Scholar

46 Abraham, E. P. et al. , ‘Nitrogenous Character of Penicillin’, Nature 149 (1942): 356CrossRefGoogle Scholar, and Abraham, E. P. and Chain, E., ‘Purification and Some Physical and Chemical Properties of Penicillin’, Brit. J. Exp. Path. 23 (1942): 108.Google Scholar

47 Alicino, Joseph F., ‘The Discovery of Sulfur in Penicillin’, Arch. Biochem. 27 (1950): 221–2.Google ScholarPubMed

48 See Abraham, E. P., ‘The Chemistry of Penicillin: Historical Introduction’, in Antibiotics, 2 vols., eds. Florey, H. W. et al. (London: Oxford University Press, 1949), vol. 2, p. 770Google Scholar, and Clarke, Hans T., Johnson, John R., and Robinson, Robert, ‘Brief History of the Chemical Study of Penicillin’, in The Chemistry of PenicillinGoogle Scholar, eds. idem. (Princeton: Princeton University Press, 1949), p. 3.

49 The strain NRRL 832 was part of the Northern Regional Research Laboratory's culture collection, and had been the strain used for penicillin production before the discovery of a higher yielding strain in a Peoria market. See Coghill, , ‘Penicillin’, 590.Google Scholar

50 Coghill, , ‘Report of a Trip’, pp. 8–9Google Scholar, and Richards, A. N. to Wintersteiner, , Folkers, , and Stodola, , 08 12, 1943Google Scholar (NA, NRRL Papers, copy in KRF). The ‘reports’, which are cited by dates in parentheses following the relevant work, refer to progress reports forwarded to the Penicillin Producer's Conference or the Committee for Penicillin Synthesis of the Medical Research Council, in the case of British workers, or reports filed with the Committee on Medical Research for the American researchers.

51 See, eg., Wintersteiner, O. et al. , ‘Isolation and Characterization of the Various Penicillins’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), p. 85Google Scholar; Abraham, , ‘Chemistry of Penicillin’, p. 770Google Scholar; and Wintersteiner, Oskar and MacPhillamy, Harold B., ‘Method of Obtaining a Crystalline Sodium Penicillin’, U. S. Patent 2,461,949, patented 02 15, 1949, col. 2, lines 9–13Google Scholar: ‘It is the object of this invention to provide highly active, stable, nonhygroscopic sodium-penicillin G, and a method of preparing it—especially to provide pure, crystalline sodium penicillin G, and a method of obtaining it.’

52 Sheehan, John C., personal communications, 11 19 and 24, 1981Google Scholar. See also Sheehan, John C., Mader, W. J., and Cram, Donald J., ‘A Chemical Assay Method for Penicillin G’, J. Am. Chem. Soc. 68 (1946): 2407.CrossRefGoogle ScholarPubMed

53 Some groups had earlier isolated samples of very high purity. For example, the Northern Regional Research Laboratory isolated preparations as high as 1850 u/mg. by April of 1943, and Imperial Chemical Industries in England reported, by July, 1943, purifications as great as 2000 u/mg. But these were exceptional cases in these laboratories. Squibb, on the other hand, consistently isolated penicillin samples of about 1500–2000 u/mg. (depending on, e.g., the solvents used). See Coghill, Robert D. to Richards, A. N., 04 12, 1943 (NA, NRRL Papers, copy in KRF)Google Scholar; Coghill, , ‘Report of a trip’, p. 9Google Scholar; Wintersteiner, et al. , ‘Characterization of Penicillins’, p. 87Google Scholar; and Wintersteiner and MacPhillamy, ‘Crystalline Penicillin’, which lists several examples of their purification.

54 Richards, to Wintersteiner, , Folkers, , and Stodola, , 08 12, 1943Google Scholar; Green, and Covell, , Medical Research, p. 316Google Scholar; Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 4Google Scholar; Abraham, , ‘Chemistry of Penicillin’, pp. 770–1Google Scholar; and Richards, , ‘Production of Penicillin’, 445.Google Scholar

55 Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 4Google Scholar, and Abraham, , ‘Chemistry of Penicillin’, p. 771.Google Scholar

56 Abraham, and Chain, , ‘Physical and Chemical Properties’, 114.Google Scholar

57 Ninhydrin is a compound that reacts with an alpha amino acid to form a blue complex. In the Van Slyke test, free amino groups are liberated as nitrogen gas in the presence of nitrous acid:

58 Abraham, E. P. et al. , ‘Penicillamine, a Characteristic Degradation Product of Penicillin’, Nature 151 (1943): 107CrossRefGoogle Scholar. Curiously, the Oxford group did get a positive test with ferric chloride in this paper, indicating the presence of sulfur in a free thiol group. But they did not include sulfur in either of their formulae. Perhaps they, like the Squibb group, rejected the possibility of the presence of sulfur because earlier publications claimed sulfur was not a part of the penicillin molecule.

59 Abraham, E. P. et al. , ‘The Earlier Investigations Relating to 2-Pentenylpenicillin’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), p. 15Google Scholar; Abraham, , ‘Chemistry of Penicillin’, p. 770Google Scholar; Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 3Google Scholar; Green, and Covell, , Medical Research, p. 315.Google Scholar

60 Abraham, et al. , ‘Earlier Investigations’, p. 15Google Scholar; Abraham, , ‘Chemistry of Penicillin’, p. 771Google Scholar; Green, and Covell, , Medical Research, p. 315.Google Scholar

61 Abraham, et al. , ‘Earlier Investigations’, pp. 15–6Google Scholar, and Green, and Covell, , Medical Research, p. 315.Google Scholar

62 Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, pp. 4–5Google Scholar, and Taylor, T. W. J. (Secretary, British Central Scientific Office) to Major, R. H. (of Merck), Harrop, George (from Squibb), and Coghill, R. D., 10 2, 1943 (NA, NRRL Papers, copy in KRF)Google Scholar. Chain, E., ‘The Components of the Penicillin Molecule’, in Antibiotics, 2 vols., eds. Florey, H. W. et al. (London: Oxford University Press, 1949), vol. 2, pp. 824–5Google Scholar, presents the first synthesis of penicillamine by the Oxford workers, and several subsequent syntheses by other groups.

63 Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 5.Google Scholar

64 For example, see Abraham, and Chain, , ‘Properties of Penicillin’, 114Google Scholar, and Coghill, , ‘Report of a trip’, p. 11.Google Scholar

65 Chain, , ‘Penicillin Molecule’, pp. 826–8Google Scholar; Abraham, , ‘Chemistry of Penicillin’, pp. 771–2Google Scholar; and Green, and Covell, , Medical Research, pp. 316–7.Google Scholar

66 See Abraham, and Chain, , ‘Properties of Penicillin’, 114Google Scholar, and Coghill, , ‘Report of a trip’, p. 11.Google Scholar

67 Chain, , ‘Penicillin Molecule’, p. 839Google Scholar; Abraham, , ‘Chemistry of Penicillin’, pp. 772–3Google Scholar; Green, and Covell, , Medical Research, p. 320Google Scholar; and Mozingo, Ralph and Folkers, Karl, ‘The Penilloic and Penicilloic Acids and Their Derivatives and Analogs’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), p. 542.Google Scholar

68 See Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 7Google Scholar; Abraham, , ‘Chemistry of Penicillin’, pp. 773–4Google Scholar; and Van Itallie, Philip H., ‘Presence of Nitrogen In Pure Penicillin Is Doubted by Chemists’, Drug Trade News, 09 27, 1943 (clipping in KRF).Google Scholar

69 Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 5Google Scholar; Abraham, , ‘Chemistry of Penicillin’, p. 773Google Scholar; Florey, and Abraham, , ‘Penicillin at Oxford’, 315Google Scholar; and Green, and Covell, , Medical Research, pp. 317–8.Google Scholar

70 Johnson, J. R., Woodward, R. B., and Robinson, R., ‘The Constitution of the Penicillins’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), pp. 453–4Google Scholar; Abraham, , ‘Chemistry of Penicillin’, pp. 776–8Google Scholar; Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 8Google Scholar; and Green, and Covell, , Medical Research, p. 320.Google Scholar

71 Abraham, , ‘Chemistry of Penicillin’, pp. 777–8Google Scholar; Green, and Covell, , Medical Research, pp. 332–3Google Scholar; and Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 8.Google Scholar

72 Hodgkin received the Nobel Prize for Chemistry in 1964 for her work in solving the structures of complex organic molecules—including penicillin.

73 Hodgkin, Dorothy Crowfoot, ‘The X-ray Analysis of the Structure of Penicillin’, Adv. Sci. 6 (1949): 85–9.Google ScholarPubMed

74 On some of the failed attempts to synthesize penicillin, see Bachmann, W. E. and Cronyn, M. W., ‘Attempted Syntheses of Penicillins’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), pp. 854–7Google Scholar; Ballard, S. A., Melstrom, D. S., and Smith, C. W., ‘The Chemistry of Beta-Lactams’Google Scholar, in ibid., pp. 987–91; Chain, E., ‘Attempts to Synthesize the Penicillins’, in Antibiotics, 2 vols., eds. Florey, H. W. et al. (London: Oxford University Press, 1949), vol. 2, pp. 957–9Google Scholar; and Abraham, , ‘Chemistry of Penicillin’, pp. 780–1.Google Scholar

75 Merck, report of 01 31, 1944Google Scholar, quoted in du Vigneaud, V., Wood, J. L., and Wright, M. E., ‘The Condensation of Oxazolones and D.-Penicillamine and the Resultant Antibiotic Activity’, in The Chemistry of Penicillin, eds. Clarke, Hans T., Johnson, John R., and Robinson, Robert (Princeton: Princeton University Press, 1949), p. 893Google Scholar. Two months later a group at Oxford, with a slightly different oxazolone, also synthesized benzylpenicillin (report of March 27, 1944).

76 Harris, Stanton A. and Folkers, Karl, ‘Production of Penicillin-G’, U. S. Patent 2,480,466, patented 08 30, 1949, cols. 2–3Google Scholar, and Green, and Covell, , Medical Research, p. 324.Google Scholar

77 See du Vigneaud, , Wood, , and Wright, , ‘Condensation of Oxazolones and D-Penicillamine’, p. 894, Figure 1.Google Scholar

78 Ibid., pp. 893–4; du Vigneaud, Vincent et al. , ‘Synthetic Penicillin’, Science 104 (1946): 432CrossRefGoogle ScholarPubMed; Chain, , ‘Attempts to Synthesize’, pp. 960–1Google Scholar; and Abraham, , ‘Chemistry of Penicillin’, pp. 781–2.Google Scholar

79 Chain, E. et al. , ‘Penicillinase’, in Antibiotics, 2 vols., eds. Florey, H. W. et al. (London: Oxford University Press, 1949), vol. 2, p. 1090Google Scholar; du Vigneaud, , Wood, , and Wright, , ‘Condensation of Oxazolones and D-Penicillamine’, p. 894Google Scholar; du Vigneaud, et al. , ‘Synthetic Penicillin’, 432Google Scholar; Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 9Google Scholar; and Chain, , ‘Attempts to Synthesize’, p. 960.Google Scholar

80 du Vigneaud, et al. , ‘Synthetic Penicillin’, 432.Google Scholar

81 Ibid., 433, and ‘Synthetic Penicillin’, Newsweek, 11 11, 1946, pp. 66, 68Google Scholar. On the apparatus and method du Vigneaud and his associates employed to isolate the synthetic material, see Craig, Lyman C., ‘Identification of Small Amounts of Organic Compounds by Distribution Studies. II. Separation by Counter-Current Distribution’, J. Biol. Chem. 155 (1944): 519–34.Google Scholar

82 du Vigneaud, et al. , ‘Synthetic Penicillin’, 432.Google Scholar

83 Sheehan, , personal communication, 11 19, 1981.Google Scholar

84 ‘Penicillin Synthesis Not “Just Around Corner”’ (see n. 10). On the optimism that many shared regarding a rapid and commercially successful synthesis of penicillin, see the concluding section of this paper.

85 ‘Minutes of the Meeting of the Penicillin Advisory Group on June 7th, 1945, At 1530 P Street, N. W., Washington, D. C.’ (NA, RG 227, OSRD, CMR, General Correspondence, ‘Penicillin Allocation and Delivery Figures, WPB’, copy in KRF).

86 U. S. Department of Commerce, Office of Domestic Commerce, Chemicals and Drugs Section, Chemicals and Drugs, 03, 1949, p. 37Google Scholar; Foster, Jackson W., Chemical Activities of Fungi (New York: Academic Press, 1949), p. 602Google Scholar; Federal Trade Commission, Report on Antibiotics, pp. 54–5Google Scholar; Perlman, , ‘Mycological Aspects’, 458Google Scholar; and Raper, Kenneth B., ‘Penicillin’, in The Yearbook of Agriculture, 1943–1947 (Washington, D. C.: Government Printing Office, 1947), p. 708.Google Scholar

87 Federal Trade Commission, Report on Antibiotics, p. 347.Google Scholar

88 Clarke, , Johnson, , and Robinson, , ‘Chemical Study of Penicillin’, p. 6Google Scholar; Baxter, James Phinney III, Scientists Against Time (Boston: Little, Brown, 1946), p. 351Google Scholar; and Florey, and Abraham, , ‘Penicillin at Oxford’, 313.Google Scholar

89 Clarke, , Johnson, , and Robinson, , Chemistry of Penicillin, pp. 1056–9Google Scholar. Penillic acid is a degradation product from penicillin, which chemists at the Wellcome Chemical Research Laboratories isolated shortly after Oxford workers isolated penicillamine; see Duffin, W. M. and Smith, S., ‘Penillic Acid, and Optically Active Acid from Penicillin’, Nature 151 (1943): 251CrossRefGoogle Scholar. Isopenillic acid is a rearranged product of penillic acid.

90 ‘Sheehan, , Clark, John’, in Modern Scientists and Engineers, 3 vols. (New York: McGraw-Hill, ca, 1980), vol. 3, pp. 105–6Google Scholar (autobiographical); ‘Pure Chemistry Award Goes to Sheehan for Penicillin Work’, Chem. Eng. News 29(1951): 1006Google Scholar; ‘Sheehan, John C.’, Chem. Eng. News 37 (no. 16) 1959: 43Google Scholar; and ‘Sheehan, , Clark, John’, American Men and Women of Science, Physical and Biological Sciences, 14th ed., 8 vols., ed. Jaques Cattell Press (New York and London: R. R. Bowker, 1979), vol. 6, p. 4609.Google Scholar

91 Sheehan, , personal communication, 11 19, 1981Google Scholar, and idem, ‘Beta-Lactam Antibiotics—Historical Perspective’, in Beta-Lactam Antibiotics: Mode of Action, New Developments, and Future Prospects, ed. Salton, Milton R. J. (New York: Academic Press, 1981), p. 11.Google Scholar

92 Sheehan, , ‘Beta-Lactam Antibiotics’, p. 11Google Scholar; idem, ‘The Chemistry of Synthetic and Semisynthetic Penicillins’, Ann. N. Y. Acad. Sci. 145 (1967): 217–8, 221 n. 11, and 222Google Scholar; idem, ‘The Synthetic Penicillins’, in Molecular Modification in Drug Design, Advances in Chemistry Series 45 (Washington: American Chemical Society, 1964), pp. 15 and 24Google Scholar; and idem, personal communication, Nov. 19, 1981. Sheehan was not the only one who hoped to modify the penicillin molecule. Indeed, this modification was a desire of chemists ever since the structure of the compound became known. However, only Sheehan attempted modification through synthesis; others tried to improve penicillin via fermentation. Cf. Chain, E. B., ‘Penicillinase-Resistant Staphylococci’, in Resistance of Bacteria to the Penicillins, eds. de Reuck, A. V. S. and Cameron, Margaret P. (Boston: Little, Brown, 1962), pp. 6 and 10Google Scholar, and idem, ‘History of Penicillin Discovery’, p. 25.Google Scholar

93 Sheehan, John C. and Henery-Logan, Kenneth R., ‘The Total Synthesis of Penicillin V’, J. Am. Chem. Soc. 79 (1957): 1262–3CrossRefGoogle Scholar; idem, ‘The Total Synthesis of Penicillin V’, ibid. 81 (1959): 3089–94 (a more detailed account than the preliminary report in 1957); Sheehan, John C., ‘Production of Penicillins’, U. S. Patent 3,159,617, patented 12 1, 1964Google Scholar, col. I; and idem, personal communication, Nov. 19, 1981.

94 Birch, A. J. and Smith, Herchel, ‘Oxidative Formation of Biologically Active Compounds From Peptides’, in Ciba Foundation Symposium on Amino Acids and Peptides With Antimetabolic Activity, eds. Wolstenholme, G. E. W. and O'Connor, Cecilia M. (Boston: Little, Brown, 1958), pp. 257–8Google Scholar (Sheehan's comments in the discussion of this article), and Sheehan, John C. and Henery-Logan, Kenneth R., ‘A General Synthesis of the Penicillins’, J. Am. Chem. Soc. 81 (1959): 5838–9.CrossRefGoogle Scholar

95 Lein, Joseph, ‘The New Semisynthetic Penicillins’, in The History of Penicillin Production, Chemical Engineering Progress Symposium Series No. 100, Vol. 66, ed. Elder, Albert L. (New York: American Institute of Chemical Engineers, 1970), pp. 66–7Google Scholar; Batchelor, F. R. et al. , ‘Synthesis of Penicillin: 6-Aminopenicillanic Acid in Penicillin Fermentations’, Nature 183 (1959): 257–8CrossRefGoogle ScholarPubMed; Chain, , ‘Penicillina-se-Resistant Penicillins’, pp. 7–8, 12–14Google Scholar; idem, ‘History of Penicillin Discovery’, pp. 25–7.Google Scholar

96 See Sheehan, , ‘Beta-Lactam Antibiotics’, pp. 11–12Google Scholar; idem, ‘Synthetic and Semisynthetic Penicillins’, 216Google Scholar; idem, ‘Production of Penicillins’, cols. 2 and 6–8 (Sheehan's claims for different methods to convert 6-APA to penicillins)Google Scholar; and idem, personal communication, Nov. 19, 1981. Sheehan converted 6-APA to penicillin in yields of 77–79%. See Sheehan, and Henery-Logan, , ‘General Synthesis of Penicillins’, 5839.Google Scholar

97 See Elder, , ‘Role of Government in Penicillin Program’, p. 4Google Scholar; Richards, , ‘Production of Penicillin’, 445Google Scholar; and Chain, Ernst B., ‘Academic and Industrial Contributions to Drug Research’, Trueman Wood Lecture delivered to the Royal Society of Arts, London, 06 19, 1963Google ScholarPubMed, excerpted in Private Practice, 05 1979, p. 52Google Scholar. Sheehan, John C., ‘Beta-Lactam Antibiotics’, p. 10Google Scholar, claims that at least 1000 chemists were involved in the wartime work.

98 This does not include the $30,000 which the government spent on the preparation of the monograph, The Chemistry of Penicillin, a summary of all work done during the war. See Federal Trade Commission, Report on Antibiotics, pp. 48–9.Google Scholar

99 ‘Merck’, Fortune, 06, 1947, p. 107Google Scholar, and Helfand, et al. , ‘Wartime Development of Penicillin’, p. 48.Google Scholar

100 Coghill, to Richards, , 04 12, 1943Google Scholar; Coghill, Robert D. to Clarke, Hans T., 04 25, 1944Google Scholar (NA, NRRL Papers, copy in KRF); and ‘The Synthesis of Penicillin’, 01 1, 1944Google Scholar [a six-page study by the NRRL on the advantages and disadvantages of their taking up the study of the synthesis of penicillin] (NA, NRRL Papers, copy in KRF), p. 1.

101 Quoted in Federal Trade Commission, Report on Antibiotics, p. 347.Google Scholar

102 For example, see Stafford, Jane, ‘More Penicillin Coming’, Science News Letter, 12 4, 1943, p. 363Google Scholar, and Edler, Albert L. to Richards, A. N., 10 9, 1943Google Scholar (NA, RG 227, OSRD, CMR, ‘Penicillin-WPB’, copy in KRF).

103 Stewart, , Organizing Research, p. 107Google Scholar; Stafford, , ‘More Penicillin Coming’, p. 363Google Scholar; Wuest, to Richards, , 11 4, 1943Google Scholar; ‘Synthesis of Penicillin’, p. 2Google Scholar; ‘Merck’, p. 109Google Scholar; ‘Synthetic Penicillin’, p. 68Google Scholar; and ‘Squibb Chairman Announces Isolation of Pure Penicillin’, Drug Trade News, 10 25, 1943 (clipping in KRF).Google Scholar

104 Wuest, to Richards, , 11 4, 1943.Google Scholar

105 Merck and Co., Vitamins in Nutrition (Rahway, N. J.: Merck, c. 1941), p. 2Google Scholar, and ‘Merck’, pp. 107, 109. However, Merck still had some reservations about committing itself to synthesis, as late as the Fall of 1942. See Merck, , Minutes of the meeting of the Chemical Research Committee, 10 12, 1942, p. 496 (Merck Archives, Rahway, N. J., copy in KRF).Google Scholar

106 See Waterman, Robert E. to Richards, A. N. and Wilson, Carroll L., 08 19, 1943Google Scholar (NA, RG 227, OSRD, Office of the Director, Special Subject File, ‘Penicillin’, Feb.–Sept. 1943, copy in KRF), and Coghill, to Richards, , 04 12, 1943.Google Scholar

107 Sheehan, , ‘Beta-Lactam Antibiotics’, p. 10.Google Scholar

108 Merck, , Minutes of the meeting of the Chemical Research Committee, 12 21, 1942, p. 511Google Scholar (Merck Archives, Rahway, N. J., copy in KRF); Herrick, H. T. (Director, NRRL) to Richards, A. N., 07 16, 1943Google Scholar (NA, NRRL Papers, copy in KRF); Richards, A. N. to Herrick, H. T., 07 23, 1943Google Scholar, (NA, NRRL Papers, copy in KRF); and Green, and Covell, , Medical Research, p. 313.Google Scholar

109 Clarke, Hans T. to Coghill, R. D., 04 22, 1944 (NA, NRRL Papers, copy in KRF)Google Scholar; Coghill, to Clarke, , 04 25, 1944Google Scholar; and Clarke, H. T. to Richards, A. N., 05 3, 1944 (NA, NRRL Papers, copy in KRF).Google Scholar

110 See, e.g., Elder, , ‘Role of Government in Penicillin Program’, p. 4Google Scholar; cf. Schmidt, Carl F., ‘Alfred Newton Richards’, Biographical Memoirs of the N. A. S. 42 [1971]: 303–4Google ScholarPubMed. See also ‘Synthesis of Penicillin’, pp. 3–5.Google Scholar

111 Federal Trade Commission, Report on Antibiotics, pp. 48–9.Google Scholar

Bibliographic Note: Some useful sources on the organization of penicillin research during World War II are Stewart, Irvin, Organizing Scientific Research for War (Boston: Little Brown, 1948)Google Scholar; Andrus, E. C. et al. , Advances in Military Medicine, 2 vols. (Boston: Little Brown, 1948)Google Scholar; Green, F. H. K. and Covell, Gordon, Medical Research (London: Her Majesty's Stationery Office, 1953)Google Scholar; Mellanby, Edward, ‘Medical Research in Wartime’, Brit. Med. J. 2 (1943): 351–6Google ScholarPubMed; and the papers of the Office of Scientific Research and Development, housed in the National Archives, Record Group 227. Stewart, who was the Executive Secretary to the OSRD, gives an administrative history of that organization. His chapters on the OSRD(3), Committee on Medical Research (7), and liaison with allied governments (11) present a valuable background to the penicillin synthesis program. Advances in Military Medicine is a thorough compilation of the work of the CMR during the war. The two chapters on penicillin (52 and 53) contain little on the chemical work. However A. N. Richards, Chairman of the CMR, presents a good summary of CMR-sponsored activities (including research on penicillin) in the Foreward to Advances. Similarly, Green and Covell's Medical Research is about the work of the British Medical Research Council. The first chapter is on the MRC's wartime organization of research, and the book also contains a discussion of the chemistry of penicillin, dealing largely with the British work. Sir Edward Mellanby's article is also useful on the functions of the MRC. The OSRD papers contain a great deal of valuable information on the organization of research in the United States. Notably, one can trace the evolution of the penicillin synthesis program from the recommendations of drug and chemical company heads, as well as others. Note that all of the cited material from the National Archives and Merck Archives has been copied and deposited in the Kremers Reference Files by David L. Cowen, and the author has utilized these photocopies in the research for this paper.

The most important source on the wartime chemical study of penicillin is Clarke, Hans T., Johnson, John R., and Robinson, Robert, eds., The Chemistry of Penicillin (Princeton: Princeton University Press, 1949)CrossRefGoogle Scholar. This study summarizes all of the work of American and British chemists, and provides references to the appropriate progress reports filed with the OSRD in the United States and the MRC in Great Britain. The broader work by a group at Oxford, Florey, H. W. et al. , Antibiotics, 2 vols. (London: Oxford University Press, 1949)Google Scholar, is also useful, especially on the British work. Several chapters in the second volume (20–29) are devoted to the chemistry and synthesis of penicillin. Because of the length of The Chemistry of Penicillin (1094 pages) and Antibiotics (the relevant chapters number about 200 pages), two less detailed chapters from these studies may be more convenient: Clarke, Hans T., Johnson, John R., and Robinson, Robert, ‘Brief History of the Chemical Study of Penicillin’, in The Chemistry of Penicillin, pp. 3–9Google Scholar; and Abraham, E. P., ‘The Chemistry of Penicillin. Historical Introduction’, in Antibiotics, vol. 2, pp. 768–83Google Scholar. Much of Sheehan, John C.'s earlier work is published in a series of eight articles under the common title, ‘The Synthesis of Substituted Penicillins and Simpler Structural Analogs’, in the Journal of the American Chemical Society between 1951 and 1954Google Scholar. Sheehan has also written a semi-popular account of the penicillin synthesis program and of his own work, The Enchanted Ring: The Untold Story of Penicillin (Cambridge, Mass.: M.I.T. Press, 1982).Google Scholar