History of Medicine

A CONTROVERSIAL NOBEL PRIZE

     Few would dispute that Nobel Prizes in the sciences are seldom mistakenly awarded. Occasionally, but only occasionally, the prize has been viewed later as inappropriate. One such instance was the award made to Dr. Johannes A. G. Fibiger, in 1926, for his work showing that intestinal worms could cause cancer. Fibiger’s conclusions eventually proved invalid but his research and life story are worth reviewing.

     Fibiger was born in Denmark in 1867. He received his medical degree from the University of Copenhagen and later studied

Johannes Fibiger (Wikipedia and National
Library of Medicine)

bacteriology in Germany. At the age of 33 he was named director of the Institute of Pathological Anatomy at the University of Copenhagen, a post he held until his death 28 years later.

     In 1907 Fibiger noticed stomach tumors in wild rats and on sectioning found small roundworms inside the growths. He learned that the worms, which he named Spiroptera carcinoma (now called Gongylonema neoplastica), were common in cockroaches, existing as a larval form in their muscles. He fed cockroaches infected with larvae to rats and produced stomach tumors, though feeding adult worms produced none. He reported the results in 1913 and the work was considered a breakthrough. However, criticisms of the report came quickly, centered mainly around whether the histology was consistent with cancer. Fibiger reported metastases in some rats but again the histology was disputed. Other workers could not easily duplicate the findings.

     In 1926 Fibiger and Katsusaburo Yamagiwa (who had induced cancer by painting coal tar on rabbit ears) were considered jointly for the Nobel Prize in medicine. No decision could be reached, however, and the prize was postponed. It was finally given to

Nobel Prize medal (Wikipedia)

Fibiger alone in 1927. The 1927 prize was awarded at the same time to Julius Wagner-Jauregg for his discovery of the helpful effect of malaria in treating tertiary syphilis (also considered a mistake by some). The staff at the Karolinska Institute, that awards the prize, commented on Fibiger’s work that “It was thus shown authoritatively not that cancer is always caused by a worm, but that it can be provoked by an external stimulus. For this reason alone, the discovery was of incalculable importance.” In his acceptance speech Fibiger acknowledged that helminthes occupied “only a modest place among the causes of neoplasms among humans”, adding that physical and chemical influences and “endogenic and exogenic” factors all played a role.

     How did the Nobel committee make the decision to award Fibiger the prize? Several seasoned pathologists had agreed with Fibiger’s histologic diagnosis of cancer, though today it would be considered hyperplasia (non-cancerous excessive growth). Cancer was known to be more common in certain occupations, such as chimney sweepers, chemical factory workers, and after radiation exposure but laboratory attempts at cancer production had generally been unsuccessful, Katsusaburo’s work being an exception. Thus the work was considered a step forward. Doubters and critics of Fibiger’s work remained, however.

     In 1937 it was shown that vitamin A-deficient diets could lead to similar changes in stomach linings. Fibiger’s rats were probably fed a vitamin A-deficient diet of bread (made without milk or egg) and water. In 1952, Hitchcock and Bell repeated

Plate from Fibiger's study of rat tumors (Hathi
Trust.  Click image to enlarge)

Fibiger’s experiments using rats on and off a vitamin A-deficient diet and produced stomach lesions resembling those of Fibiger’s animals (the original slides were studied). They concluded that vitamin A deficiency was necessary for the hyperplasia-inducing effect of the worms.

     Fibiger made another contribution to medicine, perhaps a more important one from today’s perspective. In 1896-7, before his cancer work and while working as a junior physician in Copenhagen, he carried out a clinical trial of an antiserum against diphtheria developed by Behring and Kitasato. (Fibiger had studied earlier under Koch and Behring.) Antiserum trials were successful in animals, but in humans had yielded uncertain results. Fibiger devised a randomized trial whereby children admitted on alternate days were treated alternately with conventional means (painting the throat with silver nitrate or tar oil) or conventional means plus antiserum. The study lasted one year. Eight of 239 in the serum group and 30 out of 245 in the control group died (the epidemic had a fairly low mortality rate). 60% developed serum sickness. The X² test, developed two years later, would have shown a p-value of 0.0003.

     This is believed to be the first controlled therapeutic trial using randomization. Fibiger consciously sought to “eliminate completely the play of chance and the influence of subjective judgment”. He realized the value of large numbers of subjects to eliminate chance variations and the value of long duration of study to eliminate seasonal variations in severity/mortality.

     The study had one immediate effect - an immediate boost in demand for serum. Surprisingly, the technique of random allocation did not catch on rapidly. Excepting a few small trials, generally with scanty details on technique, it took a major British Medical Research Council trial of streptomycin against tuberculosis in 1948 to put the technique on the map.

     Fibiger died the year after his prize was awarded. He had given up working with parasites and was working on coal tar painting to induce cancer. He was a member of numerous prestigious societies, was well-regarded by his colleagues as a careful researcher, and probably would have changed his mind about the stomach tumors as new evidence accumulated. He worked at a time when knowledge of cancer and histology was still patchy. Unfortunately he entered a blind alley, a hazard threatening many an investigator.

SOURCES

Stolley, PD and Lasky, T. “Johannes Fibiger and His Nobel Prize for the Hyposthesis that a Worm Causes Stomach Cancer”. 1992; Ann Internal Med 116: 765.

Bullock, FD and Rohdenburg, GL. “Experimental ‘Carcinomata’ of Animals and their Relation to True Malignant Tumors. 1917; J Cancer Research 3: 227.

 Fibiger, J. “On Spiroptera Carcinomata and their Relation to True Malignant Tumors; with Some Remarks on Cancer Age” 1919; J Cancer research 4: 367.

 Hitchcock, CR and Bell, ET. “Studies on the Nematode Parasite, Gongylonema neoplasticum (Spiroptera neoplasticum), and Avitaminosis A in the Forestomach of Rats: Comparison with Fibiger’s Results. 1952; J National Cancer Institute 12: 1345.

Hróbjartsson, A, et al. “The Controlled Clinical Trial Turns 100 Years: Fibiger’s Trial of Serum Treatment of Diphtheria” 1998; BMJ 317: 1243.

Nobel web site: https://www.nobelprize.org/prizes/medicine/1926/fibiger/biographical/. His biography and acceptance speech are both there.