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
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.
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| Johannes Fibiger (Wikipedia and National Library of Medicine) |
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
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.
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| Nobel Prize medal (Wikipedia) |
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
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.
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| Plate from Fibiger's study of rat tumors (Hathi Trust. Click image to enlarge) |
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.
