Diphtheria research

Fibiger's doctoral research was on diphtheria. He developed more efficient method of growing bacteria in a laboratory setting. He discovered that there were two different forms (strains) of the diphtheria bacillus (Corynebacterium diphtheriae) that produce two different symptoms, now called nasopharyngeal and cutaneous diphtheria. He also produced a blood serum against the disease.^[4] He was known for his methodological system of research. One of his experiments from 1898 in which he tested the blood serum for diphtheria is regarded by some as the first controlled clinical trial.^[3] While working as a Junior Physician in Blegdamshospitalet, he tested his diphtheria serum among hundreds (484) patients. As would be in modern clinical trial, he separated serum-treated and untreated patients, and found that more of untreated patients died than the treated ones. According to an article in The British Medical Journal in 1998:

[Fibiger's experiment in 1898] was the first clinical trial in which random allocation was used and emphasised as a pivotal methodological principle. This pioneering improvement in methodology, combined with a large number of patients and rigorous planning, conduct, and reporting, makes the trial a milestone in the history of clinical trials.^[6]

Cancer and parasitology research

While studying tuberculosis in lab rats, Fibiger found tumors in some wild rats collected from Dorpat (officially Tartu, now in Estonia) in 1907. Rats having stomach tumour (papilloma) also had nematodes and their eggs. He found that some tumours were metastatic (cancerous). He hypothesised that the nematodes caused the stomach cancer. After years of investigation, he experimentally demonstrated in 1913 that the nematode could induce stomach cancer. He published his discovery in a series of three papers, 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) at Brussels the same year.^[7] He knew that the nematode was a new species, and provisionally named it Spiroptera carcinom in 1914. With Hjalmar Ditlevsen, of the Zoological Museum of the University of Copenhagen, he described it as Spiroptera (Gongylonema) neoplastica in 1914.^[8] Ditlevsen revised the description in 1918, and gave the final valid name Gongylonema neoplasticum.^[9] But Fibiger never used the formal scientific name, and persistently used Spiroptera carcinoma.^[10]

Fibiger's experiment was the first to show that helminth parasites can 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 demonstrated the induction of cancer (carcinoma) in rabbits. They showed that it was relatively easy to produce cancer was by painting coal-tar on the inner surface of the ear.^[11] A number independent experiments subsequently confirmed the cancer-inducing effect of coal-tar in mice.^[12] With such supporting evidence, Fibiger's work was regarded a milestone in cancer study.^[10][13]

Nomination and selection

Fibiger was nominated for the Nobel Prize in Physiology or Medicine 18 times from 1920. In 1926, he received two nominations along with Katsusaburo Yamagiwa.^[15] Folke Henschen and Hilding Bergstrand were appointed by the Nobel Committee as assessors. They disagreed on each other's conclusion. Henschen was in favour of the nomination and concluded that "the experimental carcinoma is worthy of the Nobel Prize. It should therefore be just if the prize would be divided between Johannes Fibiger, the discoverer of the experimental spiroptera carcinoma, and Katsusaburo Yamagiwa, the discoverer of the experimental tar carcinoma." But Bergstrand opposed to it, concluding that "an experimental confirmation of a previously known fact... [referring to the prevalence of cancer among chimney sweeps and factory workers, an already established medical fact at the time^[16][17]] can, in this case, not be considered... that one cannot, at this point, find 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 Nobel Prize." The Nobel Committee could not make the final decision and decided not to give the prize for 1926. In the next year, Fibiger received seven nominations, and Yamagiwa was then excluded. Instead there were two other nominees, Otto Heinrich Warburg and Julius Wagner-Jauregg. In addition to Henschen and Bergstrand, Einar Hammersten was appointed as the third assessor. On Fibiger, Bergstrand was of the same opinion, Hammersten was in favour. Hence the three nominees were recommended for the award. The Nobel Committee decided to give the 1926 prize jointly to Fibiger and Warburg, and the 1927 prize to Wagner-Jauregg. However, the authority at the Karolinska Institute disagreed with the recommendation for Warburg for undisclosed reasons, and Fibiger became the sole winner.^[18] (Warburg was eventually awarded the prize in 1931.^[10])

Posthumous criticism and disproof

Fibiger's discovery was unchallenged during his lifetime. The only serious criticism was by F. D. Bullock and G. L. Rohdenburg. In 1918, they argued that the cancerous tumours produced in Fibiger's experiments were similar to non-cancerous tumours. Such tumours easily developed in epithelial cells.^[19] Fibiger defended "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."^[7]

It was only after Fibiger's death that the importance of vitamin A in cancer development was fully appreciated. Fibiger had used rats which were fed vitamin A-less diet. It was found that Vitamin A deficiency alone can cause tumours and cancers. The parasites had merely caused the tissue irritation (chronic inflammation) that drove the damaged cells into cancer; any tissue irritation could have induced the tumours.^[20][21][22] The major challenge came from Richard Douglas Passey, with his colleagues A. Léese, and J.C. Knox. They reported a new finding in 1935 that S. carcinoma do not cause cancer in rats. They concluded that Fibiger probably had mistaken metaplasia (a non-cancerous tumour) with malignant neoplasia (true cancer).^[23] In 1937, W. Cramer experimentally showed that Fibiger's tumour were not cancerous.^[24] The final disproof was shown by Claude R. Hitchcock and E. T. Bell. In 1952, they repeated Fibiger's experiments using advanced microscopy and histology, and conclusively demonstrated that the tumours due to G. neoplasticum in rats were non-cancerous tumours. And the tumours were primarily due to vitamin A deficiency.^[25]

It is also claimed that exclusion of Yamagiwa was another mistake. Yamagiwa's work has become the primary basis for induction of tumours in cancer research.^[26] Because of this, some consider Fibiger's Nobel Prize to be undeserved particularly because Yamagiwa did not receive the prize.^[27] Encyclopædia Britannica's guide to Nobel Prizes in cancer research mentions Yamagiwa's work as a milestone without mentioning Fibiger.^[28]

Although G. neoplasticum is non-carcinogenic, other helminth parasites such as Schistosoma haematobium, Opisthorchis viverrini and Clonorchis sinensis are now established to cause cancer in humans.^[29][30]