Skip to main content
SpringerLink
Log in

Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle

  • Memories and Retrospectives
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today’s knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld’s contributions in this development, which have remained largely unknown.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Notes

  1. The phrase “the sugarcoated microbe” has been envisaged by Avery as the title of a book he wanted to write but never did. It was adopted by McCarty as a chapter title [17].

  2. Both authors of this article have been members of the scientific staff of the Rockefeller University, formerly named Rockefeller Institute for Medical Research (RIMR), New York: R.M.K. having spent a substantial part of his professional life there, K.E. several years as a junior scientist. Neither of the authors had the good fortune to know Avery while he was still an active investigator. R.M.K. met Avery in 1950 at a conference on streptococcal research at the Streptococcal Diseases Laboratory, Warren Air Force Base, Cheyenne, Wyoming. He reviewed his research on M protein isolation, a virulence factor of Group A streptococci, with both Avery and Rebecca Lancefield. Avery’s advice was: “Treat M protein more gently.” Avery retired from the RIMR and from active science in 1948. MacLeod left Rockefeller in 1941 to become professor of microbiology at New York University School of Medicine. McCarty remained at Rockefeller University for many years until his death in 2005. He was active during retirement in research, editing the Journal of Experimental Medicine, and many related activities. Both of the authors had the good fortune to work in close association with McCarty—Mac as he was known to all his associates—whose laboratory and office were next door to ours. He was our respected teacher and advisor in many aspects of science and everyday life. It is perhaps not surprising that, as a result, both of us developed a deep and lasting interest in the concepts and experiments that eventually led to the identification of DNA as the transforming principle. This discovery, published in 1944, became the basis of today’s knowledge that genes consist of DNA, and is perhaps the most consequential discovery in the biosciences of the twentieth century.

  3. All quotations from documents in German translated by K. E.

  4. Levinthal moved to England in 1933, and became professor of microbiology at Edinborough. His correspondence and papers were discarded after his death.

  5. This aspect was analysed in depth by Mendelson [33]: The “microbe-hunters” among microbiologist followed Robert Koch who concluded from his successful handling of the cholera epidemic of Hamburg in 1892: “Had one in Hamburg not tracked the cholera into its remotest nook and cranny in so energetic a way and rendered innocious every discoverable trace of the infectious material, then it certainly would not have been possible, in my conviction, to master the fuel that was spread over the city in such a massive way”. In contrast, Neufeld attacked this attitude by calling upon his colleagues: “…to give up at last the notion that it is their duty to track down every last bacillus (or in typhus every last louse) into its remotest nook and cranny and to kill it” [32]. Neufeld thus held what became known as the “holistic view”, i.e. the coexistence of man and microbes in some form of equilibrium, with epidemics being mere disturbances of that equilibrium. See also reference [22].

  6. M. G. Sevag described a method of deproteinizing solutions which was used by Avery et al. in the purification of the DNA fraction that had transforming activity (quoted in [11]). Neufeld was very supportive of Sevag, for example by approaching Flexner to consider one of Sevag’s papers for the Journal of Experimental Medicine.

  7. This animal model was not further pursued. It was replaced by studies on a spontaneous pneumococcal epidemic of animal house guinea pigs, in line with Neufeld's philosophy that studying natural infections was more informative than artificial animal models [22].

  8. Both reviews are transcripts of lectures given by Neufeld about a year before publication.

  9. Griffith died in 1941 during an air raid on London. No correspondence between Griffith and Neufeld in the 1930s has been found.

References

  1. Behring E (1890) Untersuchungen über das Zustandekommen der Diphterieimmunität bei Thieren. Dtsch Med Wochenschr 16:1145

    Article  Google Scholar 

  2. Behring E, Kitasato S (1890) Über das Zustandekommen der Diphterieimmunität und der Tetanusimmunität bei Thieren. Dtsch Med Wochenschr 16:1113

    Article  Google Scholar 

  3. Klemperer G, Klemperer F (1891) Versuche über Immunisierung und Heilung bei der Pneumokokkeninfektion. Berliner Klin Wochenschr 28:833–835

    Google Scholar 

  4. Fraenkel A (1886) Weitere Beiträge zur Lehre von den Mikrokokken bei der genuinen fibrinösen Pneumonie. Z Klin Med 5(6):437–458

    Google Scholar 

  5. Neufeld F, Händel L (1909) Über die Herstellung von Pneumokokkenserum und über die Aussichten einer spezifischen Behandlung der Pneumonie. Z Immunitätsforsch III:159–171

    Google Scholar 

  6. Neufeld F, Händel L (1909) Über die Entstehung der Krise bei der Pneumonie und über die Wirkung des Pneumokokkenserums. Arb Kais Gesundheitsamt 34:166–181

    Google Scholar 

  7. Neufeld F, Händel L (1909) Weitere Untersuchungen über Pneumokokken-Heilserum III Mitteilung: Über Vorkommen und Bedeutung atypischer Varietäten des Pneumokokkus. Arb Kais Gesundheitsamt 34:293–304

    Google Scholar 

  8. Podolsky SH (2006) Pneumonia before antibiotics. Johns Hopkins University Press, Baltimore

    Google Scholar 

  9. Heidelberger M, Avery OT (1923) The soluble specific substance of pneumococcus. J Exp Med 38(1):73–79

    Article  PubMed  CAS  Google Scholar 

  10. Heidelberger M, Avery OT (1924) The soluble specific substance of pneumococcus: second paper. J Exp Med 40(3):301–317

    Article  PubMed  CAS  Google Scholar 

  11. Avery OT, MacLeod CM, McCarty M (1944) Studies on the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 79(2):137–158

    Article  PubMed  CAS  Google Scholar 

  12. Dochez AR (1912) The presence of protective substances in human serum during lobar pneumonia. J Exp Med 16(5):665–679

    Article  PubMed  CAS  Google Scholar 

  13. Dochez AR, Avery OT (1915) Varieties of pneumococcus and their relation to lobar pneumonia. J Exp Med 21(2):114–132

    Article  PubMed  CAS  Google Scholar 

  14. Avery OT, Chickering HAT, Cole R, Dochez AR. (1917) Acute Lobar Pneumonia. Prevention and Serum Treatment. Monographs of the Rockefeller Institute for Medical Research No. 7

  15. Wilson GS, Miles AA (eds) (1955) Topley and Wilson’s principles of bacteriology and immunity, vol 1 and 2. Edward Arnold, London

  16. MacLeod CM, Hodges RG, Heidelberger M, Bernard WG (1945) Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J Exp Med 82:445–465

    Article  Google Scholar 

  17. McCarty M (1985) The transforming principle. Norton, New York

  18. Dubos R (1976) The professor, the institute, and DNA. Rockefeller University Press, New York

    Google Scholar 

  19. Downie AW (1972) Pneumococcal transformation—a backward view, fourth griffith memorial lecture. J Gen Microbiol 73:1–11

    Article  PubMed  CAS  Google Scholar 

  20. Olby R (1974) The path to the double helix: the discovery of DNA. Dover, New York

    Google Scholar 

  21. Griffith F (1928) The significance of pneumococcal types. J Hyg 27:113–159

    Article  PubMed  CAS  Google Scholar 

  22. Mozew C (2003) Fred Julius Neufeld (1869–1945). Sein Leben und Werk. Dissertation, University of Heidelberg

  23. Neufeld F (1946) Erinnerungen aus meiner 50jährigen Tätigkeit als Bakteriologe. Ärztl Wochenschr 1(146–150):186–189

    Google Scholar 

  24. Neufeld F (1899) Ueber die Züchtung der Typhusbacillen aus Roseolaflecken nebst Bemerkungen über die Technik bakteriologischer Blutuntersuchungen. Med Microbiol Immunol 30(1):498–510

    Google Scholar 

  25. Hinz-Wessels A (2008) Das Robert Koch-Institut im Nationalsozialismus. Kulturverlag Kadmos, Berlin

    Google Scholar 

  26. Hinz-Wessels A (2009) Das RKI unter der NS-Diktatur: Personelle, administrative und inhaltliche Umgestaltung zwischen 1933 und 1945. In: Hulverschmidt A, Laukötter A (eds) Infektion und Institution. Wallstein, Göttingen, pp 67–88

  27. http://www.rki.de/DE/Content/Institut/Geschichte/Dokumente/Geschichte_im_Ueberblick.pdf

  28. Bonah C, Gradmann C (2009) Das Robert Koch Institut als Institution zwischen Kaiserreich und Nationalsozialismus. Internationale Beziehungen, verwaltete Wissenschaft und NS-System - Ein Kommentar. In Hulverschmidt A, Laukötter A (eds) Infektion und Institution. Wallstein, Göttingen, pp 250–260

  29. Robert Koch-Institute Archive, Berlin, Germany. Fred Neufeld personal file, Fred Neufeld document collection (Uncatalogued)

  30. Rockefeller Archive Center, Simon Flexner correspondence. American Philosophical Society, Philadelphia, PA, USA

  31. Neufeld F (1927) Origin and dissemination of tuberculosis according to recent investigations. Harvey Lect 22:27–40

    Google Scholar 

  32. Neufeld F (1927) Fortschritte und Rückschritte der epidemiologischen Forschung. Dtsch Med Wochenschr 53:687–690

    Article  Google Scholar 

  33. Mendelsohn JA (1998) From eradication to equilibrium. how epidemics became complex after world war I. In: Lawrence C, Weisz G (eds) Greater than the Parts: Holism in Biomedicine, 1920–1950, Oxford University Press, New York, pp 303–331

  34. Kleine F (1947) Nachruf für Fred Neufeld. Med Mikrobiol Immunol 127:185–186

    Google Scholar 

  35. Neufeld F (1900) Ueber eine spezifische bakteriolytische Wirkung der Galle. Med Microbiol Immunol 34(1):454–464

    Google Scholar 

  36. Neufeld F (1902) Ueber die Agglutination der Pneumokokken und über die Theorien der Agglutination. Med Microbiol Immunol 40(1):54–72

    Google Scholar 

  37. Armstrong RR (1932) Immediate pneumococcal typing. Br Med J 1(3708):187–188

    Article  PubMed  CAS  Google Scholar 

  38. Logan WR, Smeall TJ (1932) A direct method of pneumococcal typing. Br Med J 1(3708):188–189

    Article  PubMed  CAS  Google Scholar 

  39. Neufeld F, Etinger-Tulczynska R (1933) Schnelldiagnose der Pneumokokkentypen aus dem Auswurf. Med Microbiol Immunol 115(2):431–435

    Google Scholar 

  40. Neufeld F, Rimpau W (1904) Über die Antikörper des Streptokokken und Pneumokokken Immunserums. Dtsch Med Wochenschr 40:1458–1460

    Article  Google Scholar 

  41. Neufeld F, Rimpau W (1905) Weitere Mittheilungen über die Immunität gegen Streptokokken und Pneumokokken. Med Microbiol Immunol 51(1):283–299

    Article  Google Scholar 

  42. Silverstein AM (1989) A history of immunology. Academic, San Diego

  43. Neufeld F (1903) Ueber Immunität und Agglutination bei Streptokokken. Med Microbiol Immunol 44(1):161–182

    Google Scholar 

  44. Kindborg A (1905) Die Pneumokokken. Zeitschr f Hyg 51:197–232

    Google Scholar 

  45. Römer P (1902) Experimentelle Grundlagen für klinische Versuche einer Serumtherapie des Ulcus corneae serpens nach Untersuchung über Pneumokokkenimmunität. Graefe’s Archiv Klin Exp Ophthalmol 54:99–200

    Article  Google Scholar 

  46. Dochez AR (1912) The occurrance and virulence of pneumococci in the circulating blood during lobar pneumonia and the susceptibility of pneumococcus strains to univalent antipneumococcus serum. J Exp Med 16(5):680–692

    Article  PubMed  CAS  Google Scholar 

  47. Neufeld F, Ungermann E (1912) Über experimentelle Erzeugung von Pneumonien bei Versuchstieren und ihre Beeinflussung durch spezifische Seren. Berl Klin Wochenschr 8:717

    Google Scholar 

  48. Neufeld F, Ungermann E (1912) Weitere Heilversuche mit Antipneumokokkenserum bei experimenteller Pneumonie. Berl Klin Wochenschr 20:1010–1011

    Google Scholar 

  49. Neufeld F, Händel L (1912) Zur Frage der Serumtherapie der Pneumonie und der Wertbestimmung des Pneumokokkenserums. Berl Klin Wochenschr 8:680–683

    Google Scholar 

  50. Tyler GE (1901) Antipneumococcic serum treatment of pneumonia, with report of cases. J Am Med Assoc 36:1540–1545

    Article  Google Scholar 

  51. Goldsborough BW (1902) A contribution to the treatment of pneumonia with antipneumococcic serum. J Am Med Assoc 38:1681–1683

    Article  Google Scholar 

  52. Anders JM (1904) Serum treatment of pneumonia. J Am Med Assoc 43:1777–1781

    Article  Google Scholar 

  53. von Hippel A (1908) Der gegenwärtige Stand der Pneumokokkus Serumtherapie des Ulcus serpens. Dtsch Med Wochenschr 34:1805–1807

    Article  Google Scholar 

  54. Beltz L (1912) Über die intravenöse Anwendung des Pneumokokkenserums. Dtsch Med Wochenschr 38:14–15

    Article  Google Scholar 

  55. Neufeld F (1922) Neue Forschungsergebnisse über Pneumonie. Dtsch Med Wochenschr 48:51–54

    Article  Google Scholar 

  56. Neufeld F (1938) Die experimentellen Grundlagen der Serumbehandlung der Pneumonie. Dtsch Med Wochenschr 64:219–221

    Article  Google Scholar 

  57. Neufeld F, Bär F (1940) Untersuchungen über die Wirkungsweise der Sulfonamide. Med Microbiol Immunol 123(1):116–125

    CAS  Google Scholar 

  58. Neufeld F, Levinthal W (1928) Beiträge zur Variabilität der Pneumokokken. Z f Immunitätsforsch 55:324–340

    Google Scholar 

  59. Wright AE (1903) A lecture on therapeutic inoculations of bacterial vaccines and their practical exploitations in the treatment of disease: delivered at the medical graduates college and polyclinic. Br Med J 1(2210):1069–1074

    Article  PubMed  CAS  Google Scholar 

  60. Wright AE (1910) Vaccine Therapy—its administration, value, and limitations. Proc R Soc Med 3(Gen Rep):1–38

    PubMed  CAS  Google Scholar 

  61. Potter NB, Avery OT (1910) Opsonins and vaccine therapy. In: Hare R (Ed) Modern Treatment. Philadelphia and New York, 1:515

  62. Lister FS (1916) An experimental study of prophylactic inoculation against pneumococcal infection in the rabbit and in man. Publ South Afr Institute Med Res 8:231–287

    Google Scholar 

  63. Centers for Disease Control and Prevention (2010) Prevention of pneumococcal disease among infants and children —use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. MMWR 59(MMWR):1–18

    Google Scholar 

  64. Centers for Disease Control and Prevention (2012) Licensure of 13-valent pneumococcal conjugate vaccine for adults aged 50 years and older. MMWR 61:394–395

    Google Scholar 

  65. Ridda I, Musher DM (2012) Is there a potential role for protein-conjugate pneumococcal vaccine in older adults? Australas Med J 5(4):231–235

    Article  PubMed  Google Scholar 

  66. Miyaji EN, Oliveira MLS, Carvalho E, Ho PL (2012) Serotype-independent pneumococcal vaccines. Cell Mol Life Sci. doi:10.1007/s00018-012-1234-8

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful for the assistance of Ms Heide Tröllmich, Archivist of the Robert Koch Institute for access by K. E. to the Fred Neufeld files containing extensive papers and correspondence, and for the assistance of Mr Charles Greifenstein, Archivist of the American Philosophical Society for access by R. M. K. to the Simon Flexner files. There is extensive correspondence in both archives between Simon Flexner and Fred Neufeld. We are grateful also to Prof. Hans-Hartmut Peter and to Sir Peter Lachmann for helpful suggestions and comments.

Author information

Authors and Affiliations

  1. Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108, Freiburg, Germany

    Klaus Eichmann

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, 16 Center Drive, Bethesda, MD, 20892, USA

    Richard M. Krause

Authors
  1. Klaus Eichmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard M. Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Eichmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eichmann, K., Krause, R.M. Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle. Cell. Mol. Life Sci. 70, 2225–2236 (2013). https://doi.org/10.1007/s00018-013-1351-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1351-z

Keywords

Search

Navigation