Skip to main content
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2001 Apr 29;356(1408):413–420. doi: 10.1098/rstb.2000.0774

Historical background.

M A Epstein 1
PMCID: PMC1088435  PMID: 11313002

Abstract

The persisting ancient view of cancer as a contagious disease ended with 19th century scientific investigations which seemed to show it was not. The resulting dogma against an infectious cause for cancer produced great prejudice in the scientific community against the first report of an oncogenic virus by Rous early in the 20th century and, even in the 1950s, against Gross's finding of a murine leukaemia virus and a murine virus causing solid tumours. The Lucké frog renal carcinoma virus was the first cancer-associated herpesvirus. Intriguingly, an environmental factor, ambient temperature, determines virus genome expression in the poikilothermic frog cells. Although an alpha-herpesvirus, Marek's disease virus of chickens shares some aspects of biological behaviour with Epstein-Barr virus (EBV) of man. Very significantly, its lymphomas are the first naturally occurring malignancy to be controlled by an antiviral vaccine, with implications for human virus-associated cancers. The circumstances and climate of opinion in which successive gamma-herpesviruses were discovered are described. The identification of EBV involved two unconventionalities: its finding in cultured Burkitt's lymphoma cells when no human lymphoid cell had ever been maintained in vitro, and its recognition in the absence of biological activity by the then new technique of electron microscopy. These factors engendered hostility to its acceptance as a new human tumour-associated virus. The EBV-like agents of Old World apes and monkeys and the T-lymphotropic gamma-herpesviruses of New World monkeys were found at about the same time, not long after the discovery of EBV. For many years these were thought to be the only gamma-herpesviruses of non-human primates; however, very recently B-lymphotropic EBV-like agents have been identified in New World species as well. Mouse herpesvirus 68 came to light by chance during a search for arboviruses and has become important as a laboratory model because of its close genetic relatedness to EBV and its comparable biological behaviour. The discovery of Kaposi's sarcoma-associated herpesvirus six years ago was made using unconventional new methods, but, unlike with EBV 30 years before, this did not hinder its acceptance. This contrast is discussed in the context of the great progress in human tumour virology which has been made in recent years.

Full Text

The Full Text of this article is available as a PDF (155.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agrba V. Z., Yakovleva L. A., Lapin B. A., Sangulija I. A., Timanovskaya V. V., Markarjan D. S., Chuvirov G. N., Salmanova E. A. The establishment of continuous lymphoblastoid suspension cell cultures from hematopoietic organs of baboon (Papio hamadryas) with malignant lymphoma. Exp Pathol (Jena) 1975;10(5-6):318–332. doi: 10.1016/s0014-4908(75)80040-8. [DOI] [PubMed] [Google Scholar]
  2. Allday M. J., Crawford D. H. Role of epithelium in EBV persistence and pathogenesis of B-cell tumours. Lancet. 1988 Apr 16;1(8590):855–857. doi: 10.1016/s0140-6736(88)91604-2. [DOI] [PubMed] [Google Scholar]
  3. Bar R. S., DeLor C. J., Clausen K. P., Hurtubise P., Henle W., Hewetson J. F. Fatal infectious mononucleosis in a family. N Engl J Med. 1974 Feb 14;290(7):363–367. doi: 10.1056/NEJM197402142900704. [DOI] [PubMed] [Google Scholar]
  4. Beral V., Peterman T. A., Berkelman R. L., Jaffe H. W. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet. 1990 Jan 20;335(8682):123–128. doi: 10.1016/0140-6736(90)90001-l. [DOI] [PubMed] [Google Scholar]
  5. Biggs P. M. The epizootiology of Marek's disease. Bibl Haematol. 1970;(36):198–209. doi: 10.1159/000391708. [DOI] [PubMed] [Google Scholar]
  6. Bittner J. J. SOME POSSIBLE EFFECTS OF NURSING ON THE MAMMARY GLAND TUMOR INCIDENCE IN MICE. Science. 1936 Aug 14;84(2172):162–162. doi: 10.1126/science.84.2172.162. [DOI] [PubMed] [Google Scholar]
  7. Blaskovic D., Stanceková M., Svobodová J., Mistríková J. Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol. 1980 Dec;24(6):468–468. [PubMed] [Google Scholar]
  8. Chang R. S., Lewis J. P., Abildgaard C. F. Prevalence of oropharyngeal excreters of leukocyte-transforming agents among a human population. N Engl J Med. 1973 Dec 20;289(25):1325–1329. doi: 10.1056/NEJM197312202892501. [DOI] [PubMed] [Google Scholar]
  9. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  10. Churchill A. E., Biggs P. M. Agent of Marek's disease in tissue culture. Nature. 1967 Jul 29;215(5100):528–530. doi: 10.1038/215528a0. [DOI] [PubMed] [Google Scholar]
  11. Churchill A. E., Payne L. N., Chubb R. C. Immunization against Marek's disease using a live attenuated virus. Nature. 1969 Feb 22;221(5182):744–747. doi: 10.1038/221744a0. [DOI] [PubMed] [Google Scholar]
  12. EPSTEIN M. A., ACHONG B. G., BARR Y. M. VIRUS PARTICLES IN CULTURED LYMPHOBLASTS FROM BURKITT'S LYMPHOMA. Lancet. 1964 Mar 28;1(7335):702–703. doi: 10.1016/s0140-6736(64)91524-7. [DOI] [PubMed] [Google Scholar]
  13. EPSTEIN M. A., BARR Y. M. CHARACTERISTICS AND MODE OF GROWTH OF TISSUE CULTURE STRAIN (EB1) OF HUMAN LYMPHOBLASTS FROM BURKITT'S LYMPHOMA. J Natl Cancer Inst. 1965 Feb;34:231–240. doi: 10.1093/jnci/34.2.231. [DOI] [PubMed] [Google Scholar]
  14. Epstein M. A., Achong B. G., Churchill A. E., Biggs P. M. Structure and development of the herpes-types virus of Marek's disease. J Natl Cancer Inst. 1968 Sep;41(3):805–820. [PubMed] [Google Scholar]
  15. Epstein M. A. Epstein-Barr virus--is it time to develop a vaccine program? J Natl Cancer Inst. 1976 Apr;56(4):697–700. doi: 10.1093/jnci/56.4.697. [DOI] [PubMed] [Google Scholar]
  16. Epstein M. A. Vaccination against Epstein-Barr virus: current progress and future strategies. Lancet. 1986 Jun 21;1(8495):1425–1427. doi: 10.1016/s0140-6736(86)91565-5. [DOI] [PubMed] [Google Scholar]
  17. FAWCETT D. W. Electron microscope observations on intracellular virus-like particles associated with the cells of the Lucké renal adenocarcinoma. J Biophys Biochem Cytol. 1956 Nov 25;2(6):725–741. doi: 10.1083/jcb.2.6.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. FRIEND C. Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J Exp Med. 1957 Apr 1;105(4):307–318. doi: 10.1084/jem.105.4.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. GROSS L. "Spontaneous" leukemia developing in C3H mice following inoculation in infancy, with AK-leukemic extracts, or AK-embrvos. Proc Soc Exp Biol Med. 1951 Jan;76(1):27–32. [PubMed] [Google Scholar]
  20. GROSS L. A filterable agent, recovered from Ak leukemic extracts, causing salivary gland carcinomas in C3H mice. Proc Soc Exp Biol Med. 1953 Jun;83(2):414–421. doi: 10.3181/00379727-83-20376. [DOI] [PubMed] [Google Scholar]
  21. Golden H. D., Chang R. S., Prescott W., Simpson E., Cooper T. Y. Leukocyte-transforming agent: prolonged excretion by patients with mononucleosis and excretion by normal individuals. J Infect Dis. 1973 Apr;127(4):471–473. doi: 10.1093/infdis/127.4.471. [DOI] [PubMed] [Google Scholar]
  22. Greenspan J. S., Greenspan D., Lennette E. T., Abrams D. I., Conant M. A., Petersen V., Freese U. K. Replication of Epstein-Barr virus within the epithelial cells of oral "hairy" leukoplakia, an AIDS-associated lesion. N Engl J Med. 1985 Dec 19;313(25):1564–1571. doi: 10.1056/NEJM198512193132502. [DOI] [PubMed] [Google Scholar]
  23. Henle G., Henle W., Diehl V. Relation of Burkitt's tumor-associated herpes-ytpe virus to infectious mononucleosis. Proc Natl Acad Sci U S A. 1968 Jan;59(1):94–101. doi: 10.1073/pnas.59.1.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kaaden O. R., Dietzschold B. Alterations of the immunological specificity of plasma membranes from cells infected with Marek's disease and turkey herpes viruses. J Gen Virol. 1974 Oct;25(1):1–10. doi: 10.1099/0022-1317-25-1-1. [DOI] [PubMed] [Google Scholar]
  25. Kato S., Akiyama Y. Lymphoid cell lines from lymphomas of Marek's disease. IARC Sci Publ. 1975;(11 Pt 2):101–108. [PubMed] [Google Scholar]
  26. Landon J. C., Ellis L. B., Zeve V. H., Fabrizio D. P. Herpes-type virus in cultured leukocytes from chimpanzees. J Natl Cancer Inst. 1968 Jan;40(1):181–192. [PubMed] [Google Scholar]
  27. Lapin B. A. The epidemiologic and genetic aspects of an outbreak of leukemia among Hamadryas baboons of the Sukhumi monkey colony. Bibl Haematol. 1973;39:263–268. doi: 10.1159/000427851. [DOI] [PubMed] [Google Scholar]
  28. Lesnik F., Ross L. J. Immunization against Marek's disease using Marek's disease virus-specific antigens free from infectious virus. Int J Cancer. 1975 Jul 15;16(1):153–163. doi: 10.1002/ijc.2910160117. [DOI] [PubMed] [Google Scholar]
  29. Lisitsyn N., Lisitsyn N., Wigler M. Cloning the differences between two complex genomes. Science. 1993 Feb 12;259(5097):946–951. doi: 10.1126/science.8438152. [DOI] [PubMed] [Google Scholar]
  30. MOLONEY J. B. Biological studies on a lymphoid-leukemia virus extracted from sarcoma 37. I. Origin and introductory investigations. J Natl Cancer Inst. 1960 Apr;24:933–951. [PubMed] [Google Scholar]
  31. Melendez L. V., Daniel M. D., Hunt R. D., Garcia F. G. An apparently new herpesvirus from primary kidney cultures of the squirrel monkey (Saimiri sciureus). Lab Anim Care. 1968 Jun;18(3):374–381. [PubMed] [Google Scholar]
  32. Melendez L. V., Hunt R. D., King N. W., Barahona H. H., Daniel M. D., Fraser C. E., Garcia F. G. Herpesvirus ateles, a new lymphoma virus of monkeys. Nat New Biol. 1972 Feb 9;235(58):182–184. doi: 10.1038/newbio235182b0. [DOI] [PubMed] [Google Scholar]
  33. Meléndez L. V., Daniel M. D., García F. G., Fraser C. E., Hunt R. D., King N. W. Herpesvirus saimiri. I. Further characterization studies of a new virus from the squirrel monkey. Lab Anim Care. 1969 Jun;19(3):372–377. [PubMed] [Google Scholar]
  34. Meléndez L. V., Hunt R. D., Daniel M. D., García F. G., Fraser C. E. Herpesvirus saimiri. II. Experimentally induced malignant lymphoma in primates. Lab Anim Care. 1969 Jun;19(3):378–386. [PubMed] [Google Scholar]
  35. Mizell M., Toplin I., Isaacs J. J. Tumor induction in developing frog kidneys by a zonal centrifuge purified fraction of the frog herpes-type virus. Science. 1969 Sep 12;165(3898):1134–1137. doi: 10.1126/science.165.3898.1134. [DOI] [PubMed] [Google Scholar]
  36. Morgan D. G., Epstein M. A., Achong B. G., Meléndez L. V. Morphological confirmation of the herpes nature of a carcinogenic virus of primates (Herpes saimiri). Nature. 1970 Oct 10;228(5267):170–172. doi: 10.1038/228170a0. [DOI] [PubMed] [Google Scholar]
  37. Naegele R. F., Granoff A., Darlington R. W. The presence of the Lucké herpesvirus genome in induced tadpole tumors and its oncogenicity: Koch-Henle postulates fulfilled. Proc Natl Acad Sci U S A. 1974 Mar;71(3):830–834. doi: 10.1073/pnas.71.3.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nazerian K., Solomon J. J., Witter R. L., Burmester B. R. Studies on the etiology of Marek's disease. II. Finding of a herpesvirus in cell culture. Proc Soc Exp Biol Med. 1968 Jan;127(1):177–182. doi: 10.3181/00379727-127-32650. [DOI] [PubMed] [Google Scholar]
  39. Niedobitek G., Young L. S. Epstein-Barr virus persistence and virus-associated tumours. Lancet. 1994 Feb 5;343(8893):333–335. doi: 10.1016/s0140-6736(94)91167-3. [DOI] [PubMed] [Google Scholar]
  40. Okazaki W., Purchase H. G., Burmester B. R. Protection against Marek's disease by vaccination with a herpesvirus of turkeys. Avian Dis. 1970 May;14(2):413–429. [PubMed] [Google Scholar]
  41. Purtilo D. T., Cassel C. K., Yang J. P., Harper R. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet. 1975 Apr 26;1(7913):935–940. doi: 10.1016/s0140-6736(75)92004-8. [DOI] [PubMed] [Google Scholar]
  42. RAFFERTY K. A., Jr KIDNEY TUMORS OF THE LEOPARD FROG: A REVIEW. Cancer Res. 1964 Feb;24:169–185. [PubMed] [Google Scholar]
  43. STEWART S. E., EDDY B. E., BORGESE N. Neoplasms in mice inoculated with a tumor agent carried in tissue culture. J Natl Cancer Inst. 1958 Jun;20(6):1223–1243. doi: 10.1093/jnci/20.6.1223. [DOI] [PubMed] [Google Scholar]
  44. STEWART S. E., EDDY B. E., GOCHENOUR A. M., BORGESE N. G., GRUBBS G. E. The induction of neoplasms with a substance released from mouse tumors by tissue culture. Virology. 1957 Apr;3(2):380–400. doi: 10.1016/0042-6822(57)90100-9. [DOI] [PubMed] [Google Scholar]
  45. Svobodová J., Blaskovic D., Mistríková J. Growth characteristics of herpesviruses isolated from free living small rodents. Acta Virol. 1982 Jul;26(4):256–263. [PubMed] [Google Scholar]
  46. Trumper P. A., Epstein M. A., Giovanella B. C. Activation in vitro by BUdR of a productive EB virus infection in the epithelial cells of nasopharyngeal carcinoma. Int J Cancer. 1976 May 15;17(5):578–587. doi: 10.1002/ijc.2910170505. [DOI] [PubMed] [Google Scholar]
  47. Trumper P. A., Epstein M. A., Giovanella B. C., Finerty S. Isolation of infectious EB virus from the epithelial tumour cells of nasopharyngeal carcinoma. Int J Cancer. 1977 Nov 15;20(5):655–662. doi: 10.1002/ijc.2910200503. [DOI] [PubMed] [Google Scholar]
  48. Tweedell K. S. Induced oncogenesis in developing frog kidney cells. Cancer Res. 1967 Nov;27(11):2040–2052. [PubMed] [Google Scholar]
  49. Zambernard J., Vatter A. E. The effect of temperature change upon inclusion-containing renal tumor cells of leopard frogs. Cancer Res. 1966 Oct;26(10):2148–2153. [PubMed] [Google Scholar]
  50. de Schryver A., Klein G., Hewetson J., Rocchi G., Henle W., Henle G., Moss D. J., Pope J. H. Comparison of EBV neutralization tests based on abortive infection or transformation of lymphoid cells and their relation to membrane reactive antibodies (anti-MA). Int J Cancer. 1974 Mar 15;13(3):353–362. doi: 10.1002/ijc.2910130311. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society of London. Series B are provided here courtesy of The Royal Society

RESOURCES