(Fibiger & Ditlevsen, 1914) Ditlevsen, 1918
Gongylonema neoplasticum (more famously as Spiroptera carcinoma) is a roundworm parasite of rats. It was discovered by a Danish physician Johannes Fibiger in 1907. Fibiger and Hjalmar Ditlevsen made a formal description in 1914 as Spiroptera (Gongylonema) neoplastica. But Ditlevsen gave the final valid name Gongylonema neoplasticum in 1918. The nematode is transmitted between rats and cockroaches.
When Fibiger discovered the nematode in the stomach of rats, he found that the stomach had tumours. Inspired by the possible link of the nematode and tumour, he performed experiments to induce tumours with nematode infection. He published his experimental success in 1913. The nematode experiment earned Fibiger the 1926 Nobel Prize in Physiology or Medicine, but under controversial circumstances. Moreover, it was later proven that Fibiger came to a wrong conclusion, that the nematode is not carcinogenic. Erling Norrby, who had served as the Permanent Secretary of the Royal Swedish Academy of Sciences and Professor and Chairman of Vorology at the Karolinska Institute, declared Fibiger's Nobel Prize as "one of the biggest blunders made by the Karolinska Institute."
A Danish physician, Johannes Fibiger, while working as Director of the Institute of Pathological Anatomy at the University of Copenhagen, dissected some wild rats collected from Dorpat (officially Tartu, now in Estonia) in 1907. He discovered nematodes and their eggs in the stomach of rats, and more importantly, the rats had stomach tumour (papilloma). He found that some tumours were metastatic (cancerous), from which he built a hypothesis that the nematodes caused stomach cancer. After five years he experimentally demonstrated that the nematode could induced stomach cancer. He published his discovery in a series of three papers in 1913, and also presented them at the Académie Royale des Sciences et des Lettres de Danemark (Royal Danish Academy of Sciences and Letters), and Troisième Conférence Internationale pour l’Étude du Cancer (Third International Conference for Researches in Cancer [my translation]) at Brussels the same year. He knew that the nematode was a new species, and provisionally named it Spiroptera carcinom in 1914. With the help of Hjalmar Ditlevsen, of the Zoological Museum of the University of Copenhagen, he made a complete zoological description and named it Spiroptera (Gongylonema) neoplastica in 1914. Ditlevsen revised the description in 1918, and gave the final valid name Gongylonema neoplasticum.
G. neoplasticum is the gastrointestinal parasite of rats, Rattus norvegicus and R. rattus. The adult roundworms are present in the epithelium of the anterior portion of the digestive tract, including the mouth, tongue, oesophagus and fundus. The body is cylindrical and elongated with both ends narrowing down. The body covering called cuticle is regularly striated. Although they are structurally similar, male and female can be easily differentiated. An adult male is relatively smaller, measuring 1.5 cm long and 0.1-0.16 mm wide. Its posterior end is more pointed and bent inward. The tail end contains cloaca and precloacal sucker on the ventral side, which are surrounded by sensory structures called caudal papillae. Two thread-like projections spicules originate from the cloaca. The female is considerable larger, about 4–5 cm long and 0.23 mm to 0.33 mm in diameter. The tail is bluntly rounded. There is a single anus, but sucker and papillae are absent.
G. neoplasticum completes it life cycle in tow hosts, rats as definitive hosts, and cockroaches (Periplaneta) as intermediate hosts. It is hermaphrodite, and has both male and female reproductive organs in the same body. The male reproductive system consists of a single testis, vas deferens, seminal vesicles, ejaculatory duct, two spicules, gubernaculum and bursa. Female reproductive organs include a pair of ovaries, oviducts, seminal receptacle, uteri and a long oviduct, vagina and vulva. The eggs are oval shaped, and enclosed in double egg membrane. They are about 57x33 μm in diameter. Inside the membrane is an embryo. Eggs are laid in the intestine of the host and excreted along with the faeces. The infested faeces are eaten by cockroaches. Inside the cockroach, the embryonic membrane is removed liberating the embryo. The embryo move to the muscle layer where it grow into a thread-like larva after 4–5 weeks. Then after 3 weeks they undergo structural modification called moulting. After this, they become infective to rats, whenever they eat an infected cockroach.
Fibiger's experiment was the first to show that nematodes cause cancer, and that cancer (tumour) can be experimentally induced. His discovery was supported by the experiment of two Japanese scientists Katsusaburo Yamagiwa and Koichi Ichikawa in 1918. Yamagiwa and Ichikawa showed that it was possible to induce cancer (carcinoma) in rabbits, and that the simplest method was by painting coal-tar on the inner surface of the ear. They even showed that different mechanical or chemical irritation, especially the painting of coal-tar upon the inner surface of the ear was the most effective in inducing carcinoma in rabbits. A number independent experiments subsequently confirmed the cancer-inducing effect of coal-tar in mice. The importance of Fibiger's work was regarded as conclusive. He was awarded the Nobel Prize in Physiology or Medicine in 1926.
From 1920 onward, Fibiger was nominated for the Nobel Prize for Physiology or Medicine 18 times. In 1920, he received two nominations, and the nominations included Katsusaburo Yamagiwa. But the two assessors appointed by the Nobel Committee, Folke Henschen and Hilding Bergstrand could not come to a mutual agreement. Henschen was in favour of the prize for the two nominees, while Bergstrand was adamant that they did not deserve. Bergstand conclusion was that there was not "much support for the possibility that the work of Fibiger and Yamagiwa will have great importance in the solving of the riddle of cancer. Under such circumstances I do not consider these discoveries worthy of the Noble Prize." The Nobel Committee decided not to give the 1926 award. But Fibiger, without Yamagiwa, was a gain considered for the award in 1927. There were two other nominees: Otto Heinrich Warburg, for his works of cancer metabolism and respiratory enzymes, and Julius Wagner-Jauregg, for the discovery of malaria treatment. The Noble Committee resolved that Fibiger and Warburg would jointly receive the Nobel Prize for 1926, and Wagner-Jauregg for 1927. But the Karolinska Institute overruled the decision and rejected Warburg. (Warburg was eventually awarded in 1931.) Fibiger became the sole winner of the 1926 Nobel Prize in Physiology or Medicine, "for his discovery of the Spiroptera carcinoma".
Disproof of Fibiger's discovery
Fibiger's Nobel Prize discovery was worsened by the experimental refutation of his discovery. In 1918, there was a critical comment from F. D. Bullock and G. L. Rohdenburg that Fibiger could have confused cancer-like (neoplastic) tumour from true (metastatic) cancer, that he did not induce actual cancer. But Fibiger responded "That these tumors are true carcinomata cannot, thus, be doubted, and the fact that they may occur in younger animals does not diminish our right to range them among the true malignant neoplasms." After his death in 1928, there was a better understanding of the nature of cancer—on the differences of neoplastic tumour and malignant tumours (cancer), challenging the claims of Fibiger. The most important criticism was by Richard Douglas Passey, with his colleagues A. Léese, and J.C. Knox. They made experimental conclusion that the nematode could not cause cancer, and that experimentally-induced cancer was due to other factors such as vitamin A deficiency. Fibiger used vitamin A-less diet for his experimental rats, and it was by then established that vitamin A deprivation alone could induce cancer. An elaborate experiment by W. Cramer in 1937 came to the conclusion that Fibiger's tumour could not be a true cancer. A more rigorous study was done by Claude R. Hitchcock and E. T. Bell in 1952. They repeated Fibiger's experiments using advanced techniques, and concluded that the tumours induced by the nematode in rats were metaplasia, not cancer. All tumours were due to vitamin A deficiency. Systematic reanalysis of Fibiger's data also gave the same conclusion that G. neoplasticum can cause tumour, but is not carcinogenic by itself.
- Paramasvaran S, Sani RA, Hassan L, et al. (April 2009). "Endo-parasite fauna of rodents caught in five wet markets in Kuala Lumpur and its potential zoonotic implications" (PDF). Trop Biomed. 26 (1): 67–72. PMID 19696729.
- Norrby, Erling (2010). Nobel Prizes and Life Sciences. Singapore: World Scientific Publishing Co. p. 115. ISBN 978-9-81-429937-4.
- Fibiger, J. (1919). "On Spiroptera carcinomata and their relation to true malignant tumors; with some remarks on cancer age". The Journal of Cancer Research. 4 (4): 367–387. doi:10.1158/jcr.1919.367.
- Lalchhandama, K. (2017). "The making of oncology: The tales of false carcinogenic worms" (PDF). Science Vision. 17 (1): 33–52.
- Fibiger, J.; Ditlevsen, H. (1914). "Contributions to the biology and morphology of Spiroptera (Gongylonema) neoplastica n. sp.". Mindeskrift i anledning af hundredaaret for Japetus Steenstrups fødsel. 25 (1-28).
- Ditlevsen, H. (1918). "Über Gongylonema neoplasticum (Spiroptera (Gongylonema) neoplastica Fibiger et Ditlevsen)". Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene. 1. Abteilung Originale. 81: 565–576.
- Kruidenier, F. J.; Peebles, C. R. (1958). "Gongylonema of Rodents: G. neoplasticum (Redefinition); G. dipodomysis n. sp.; and G. peromysci n. sp.". Transactions of the American Microscopical Society. 77 (3): 307–315.
- Yokogawa, Sadamu (1925). "On a new species of nematode, Gongylonema orientale, found in Formosa". The Journal of Parasitology. 11 (4): 195–200. doi:10.2307/3270828.
- Ransom, B.H.; Hall, M.C. (1915). "The life-history of Gongylonema scutatum". Journal of Parasitology. 2 (2): 80–86. doi:10.2307/3271023.
- Yamagiwa, K.; Ichikawa, K. (1918). "Experimental study of the pathogenesis of carcinoma". The Journal of Cancer Research. 3 (1): 1–29. doi:10.1158/jcr.1918.1.
- Narat, J. K. (1925). "Experimental production of malignant growths by simple chemicals". The Journal of Cancer Research. 9 (1): 135–147. doi:10.1158/jcr.1925.135.
- Kuper, H.; Adami, H.-O.; Trichopoulos, D. (2000). "Infections as a major preventable cause of human cancer". Journal of Internal Medicine. 248 (3): 171–183. PMID 10971784. doi:10.1046/j.1365-2796.2000.00742.x.
- "Johannes Fibiger - Nominations". www.nobelprize.org. Nobel Media AB. Retrieved 23 April 2017.
- Stolt, CM; Klein, G; Jansson, AT (2004). "An analysis of a wrong Nobel Prize-Johannes Fibiger, 1926: a study in the Nobel archives". Advances in Cancer Research. 92: 1–12. PMID 15530554. doi:10.1016/S0065-230X(04)92001-5.
- Stolt, C.-M.; Klein, G.; Jansson, A.T.R. (2004). "An Analysis of a Wrong Nobel Prize—Johannes Fibiger, 1926: A Study in the Nobel Archives". In Woude, G.F.V.; Klein, G. Advances in cancer research. California (US): Elsevier Academic Press. pp. 1–13. ISBN 9780080522296.
- "The Nobel Prize in Physiology or Medicine 1926". www.nobelprize.org. Nobel Media AB. Retrieved 23 April 2017.
- Bullock, F. D.; Rohdenburg, G. L. (1918). "Experimental "carcinomata" of animals and their relation to true malignant tumors". The Journal of Cancer Research. 3 (3): 227–273. doi:10.1158/jcr.1918.227.
- Passey, R. D.; Leese, A.; Knox, J. C. (1935). "Spiroptera cancer and diet deficiency". Journal of Pathology and Bacteriology. 40 (1): 198–199.
- Tyson, M. D.; Smith, A. H. (1929). "Tissue changes associated with Vitamin A deficiency in the rat". The American Journal of Pathology. 5 (1): 57–70. PMID 19969830.
- Sugiura, K.; Benedict, S. R. (1930). "A critical study of vitamin A and carcinogenesis". The Journal of Cancer Research. 14 (2): 306–310. doi:10.1158/jcr.1930.306.
- Sugiura, K.; Benedict, S. R. (1930). "The influence of high fat diets on the growth of carcinoma and sarcoma in rats". The Journal of Cancer Research. 14 (2): 311–318. doi:10.1158/jcr.1930.311.
- Cramer, W. (1937). "Papillomatosis in the forestomach of the rat and its bearing on the work of Fibiger". The American Journal of Cancer. 31 (4): 537–555. doi:10.1158/ajc.1937.537.
- Hitchcock, Claude R.; Bell, E. T. (1952). "Studies on the nematode parasite, Gongylonema Neoplasticum (Spiroptera Neoplasticum), and avitaminosis a in the forestomach of rats: Comparison with Fibiger's results". Journal of the National Cancer Institute. 12 (6): 1345–1387. doi:10.1093/jnci/12.6.1345.
- Oettlé, A. G. (1962). "A historical review of past histopathological material at the South African Institute for Medical Research between 1911 and 1927". South African Medical Journal. 36 (31): 628–631.
- Clemmesen, J (1978). "Johannes Fibiger. Gongylonema and vitamin A in carcinogenesis". Acta Pathologica et Microbiologica Scandinavica. 270 (Suppl.): 1–13. PMID 362817.