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Johannes Fibiger Induces Cancer in Lab Animals and Helps Advance Cancer Research, in Particular Leading Directly to the Study of Chemical Carcinogens

Johannes Fibiger Induces Cancer in Lab Animals and Helps Advance Cancer Research, in Particular Leading Directly to the Study of Chemical Carcinogens

Overview

Johannes Andreas Grib Fibiger (1867-1928), Danish physician, pathologist, and bacteriologist, was awarded the 1926 Nobel Prize in physiology or medicine for his research on the etiology of cancer and for his discovery of a parasite that he claimed was the cause of cancer. Fibiger called the parasite, which was a nematode worm, Spiroptera carcinoma, or Spiroptera neoplastica. The organism is now regarded as a member of the genus Gongylonema. Although Fibiger's work seemed to show that nematodes caused carcinoma in rodents, other researchers were unable to confirm his results. Unfortunately, the great hope expressed in the 1920s that Fibiger's research would lead to a practical solution for the cancer puzzle proved to be unfounded. Although for many years other cancer investigators rejected his work on Spiroptera carcinoma and his general ideas about cancer, he is regarded as one of the pioneers of randomized controlled clinical trials for his work on diphtheria serum. Changing concepts of disease and recent studies of the relationship between other pathogens and cancer has led to a reevaluation of Fibiger's place in the history of medicine.

Background

Johannes Andreas Grib Fibiger was born in Silkeborg, Denmark. His father, C. E. A. Fibiger, was a local medical practitioner and his mother, Elfride Muller, was a writer. Although his father died when Johannes Fibiger was very young, Fibiger hoped to become a physician like his father. While an undergraduate at the University of Copenhagen, Fibiger became interested in bacteriology. He was awarded his bachelor's degree in 1883 and his M.D. in 1890 from the University of Copenhagen. After a period of working in hospitals and studying under Robert Koch (1843-1910) and Emil von Behring (1854-1917) in Germany, he returned to Copenhagen. From 1891-1894 he was assistant to Professor Carl Julius Salomonsen in the Department of Bacteriology of Copenhagen University. Fibiger served as an army reserve doctor at the Hospital for Infectious Diseases in Copenhagen from 1894-1897 while completing his doctoral research on the bacteriology of diphtheria. In 1895 he received his doctorate from the University of Copenhagen for a thesis on diphtheria and returned to Germany to work at the pathological institute of Johannes Orth. In 1897 Fibiger was appointed dissection assistant for the University of Copenhagen's Institute of Pathological Anatomy. In 1900 he became professor of pathology at the University of Copenhagen. He also served as Principal of the Laboratory of Clinical Bacteriology of the Army from 1890-1905. In 1905 he became Director of the Central Laboratory of the Army and Consultant Physician to the Army Medical Service.

Although Fibiger is often referred to in cautionary terms to demonstrate how researchers can leap to incorrect conclusions, he was a careful researcher and eminent scientist. His pioneering studies of randomized controlled clinical trials demonstrate this aspect of Fibiger's legacy. The British Medical Research Council's trial of streptomycin for pulmonary tuberculosis (1948) is often referred to as the first modern randomized clinical trial. However, the study of the effect of serum treatment on diphtheria published by Fibiger in 1898 was actually the first clinical trial in which randomization was recognized as a fundamental methodological principle. The Copenhagen diphtheria trial was conducted in 1896-1897. Although the results of previous trials were ambiguous and did not seem to justify the side effects caused by serum treatment, Fibiger discovered methodological deficiencies in previous trials. Fibiger believed that a rigorous new trial was necessary: his objective was to investigate the effects of serum treatment on the mortality and morbidity of patients suffering from diphtheria. From May 1896 to May 1897 patients with diphtheria were treated with diphtheria serum or with standard treatment alone. Patients were assigned to the two groups on the basis of the day of admittance to the hospital. Serum sickness occurred in 60% of the patients. Only 8 out of 239 patients in the serum treated group died; 30 out of 245 in the control group died. Epidemiologists who have examined Fibiger's trial believe that its quality was high, even when judged by modern standards. Although few physicians followed Fibiger's excellent model in future clinical trials, his results did lead to a high demand for the new serum treatment for diphtheria.

After he was appointed Professor of Pathological Anatomy and Director of the Institute of Pathological Anatomy in 1900, Fibiger initiated a new research project in tuberculosis. He was particularly interested in the relationship between human and bovine tuberculosis. Although he was also interested in cancer, he had no experimental model that could be used to solve the problem of the origins of the cancer cell. At the time, scientists could transfer cancerous tissue from one animal to another, but they lacked techniques that could reliably induce cancer in a healthy animal. Influenced by the success of bacteriology in finding the cause of so many diseases, Fibiger hoped that similar methods might provide insights into the genesis of cancer.

In 1907, while dissecting three rats that had been injected with tubercle bacilli, Fibiger found that all of these animals had papillomatous stomach cancers. Microscopic examination of the tumorous tissue revealed traces of eggs and peculiar little worms. Intrigued by these observations, Fibiger abandoned his research on tuberculosis and joined the legions of scientists who were trying to solve the problem of cancer through experimental research. His initial attempts to find similar parasites in rats failed after he had tested almost 1,000 animals. Based on reports that a tiny worm known as a nematode infested rats and cockroaches, Fibiger attempted to collect rats that subsisted largely on roaches. He found that the rats and roaches at a Copenhagen sugar refinery were infested by nematodes. About 75% of the rats were infested with the nematodes he had identified previously and 20% had stomach tumors. After isolating the parasitic nematode in question and determining that it was a new species, he passed it repeatedly from infested rats to cockroaches and then to healthy rats. Fibiger reported that these rats eventually developed tumors of the stomach. In 1913 Fibiger reported on his discovery to the Royal Danish Academy of Science. He called the nematode Spiroptera neoplastica. Fibiger thought that roaches became infested by eating rat excrement that contained the eggs of the parasite. Rodents became infected, or re-infected, by eating larvae-infested roaches. According to Fibiger, his work proved that cancers were caused by the nematodes or by chemicals released by the nematodes. In other words, chronic irritation by a foreign agent or toxin induced tumor formation.

Many investigators were skeptical, but some considered Fibiger's work quite ingenious and convincing. Fibiger was not the first to suggest that some parasite was the cause of cancer, but most of these other claims were based on poorly designed experiments and were rapidly discredited. Several scientists agreed with Fibiger's conclusion and published reports of other parasiteinduced cancer. For example, in 1920 Frederick Dabney Bullock, M. R. Curtis, and G. L. Rohdenberg reported that liver sarcoma in rats was caused by the parasite Cysticercus fasciolaris, the larval stage of Taenia crassicolis. As a new research assistant, future Nobel Laureate Gerty Cori (1896-1957) was assigned to work with a researcher in the Pathology Department of the State Institute for the Study of Malignant Diseases, in Buffalo, New York, who claimed that encapsulated Amoeba histolytica was the cause of Hodgkin's disease. By the time Fibiger was awarded the Nobel Prize, he realized that his parasites probably were not the key to the etiology of cancer. Other researchers had little or no success in duplicating Fibiger's results in their experimental animals. Some investigators found that tumors similar to those reported by Fibiger also occurred in rodents when their diet was deficient in vitamin A.

Impact

Despite the optimism and high praise expressed when Fibiger was awarded the 1926 Nobel Prize in Physiology or Medicine, his work soon subjected to sharp criticism and was then all but forgotten. Eventually, Fibiger himself suggested that some external agents might generate cancer in genetically susceptible individuals. He believed that the lasting value of his work was the demonstration that "spontaneous" cancer (tumors that were not transplanted) could be routinely produced in laboratory animals under appropriate conditions. Certainly, the hope and example generated by Fibiger's work helped open up new approaches to the experimental study of cancer. Although many lines of research had been attempted in the early twentieth century, few observers were willing to claim that any results had been of significant practical value. During the early twentieth century, older clinical observations of the development of skin cancer, such as Percivall Pott's (1714-1788) classic report of an occupational cancer, i.e., cancer of the scrotum in chimney sweeps, were confirmed and extended by laboratory research. During the nineteenth century several studies had linked cancer to external causes. Skin cancers had been associated with tar and paraffin, cancer of the lung was thought to be an occupation disease of miners, and aniline was found to cause various cancers. In 1916 Katsusaburo Yamagiwa (1863-1930) demonstrated that repeated applications of tar led to the production of skin cancer in laboratory rabbits. This extended knowledge of the etiological relationship between the incidence of tumors and exposure to certain chemicals. Exposure to x rays and radium among researchers was soon associated with the induction of cancers. Fibiger died of a heart attack shortly after he was diagnosed with colon cancer and only six weeks after participating in the Nobel Prize ceremonies.

Perhaps somewhat embarrassed by the lack of confirmation of Fibiger's cancer hypothesis, the Nobel Foundation made no other awards for cancer research for 40 years after honoring Fibiger. In 1966 the Nobel Prize was awarded to Francis Peyton Rous (1879-1970), who discovered that a virus might cause cancer, and Charles Huggins (1901-1997), who introduced hormonal treatment for prostate cancer. Subsequent recognition of the relationship between infections and certain malignant diseases has created new interest in Fibiger's work. Some researchers suggested that the tumors observed in Fibiger's experimental animals might have been caused by a virus carried by the parasite worm, even though the worm itself was not the cause of cancer. Nematodes are known to serve as carriers of various disease agents. Pathogens have been linked to other forms of cancer; for example, Schistosoma haematobium is associated with bilharzia cancer of the bladder, Spirocerca lupi appears to cause malignant neoplasms in dogs, and Helicobacter pylori has been associated with gastric ulcers and stomach cancer in humans.

LOIS N. MAGNER

Further Reading

Periodical Articles

Campbell, William C. "The Worm and the Tumor: Reflections on Fibiger's Nobel Prize." Perspective in Biology and Medicine 40, no. 4 (summer 1997): 498-506.

Clemmesen, J. Johannes Fibiger. "Gongylonema and Vitamin A in Carcinogenesis." Acta Pathologica Microbiology Scandinavia supplement 270 (1978): 1-13.

Hrobjartsson, Asbjorn; Gotzsche, Peter C; Gluud, Christian. "The Controlled Clinical Trial Turns 100 Years: Fibiger's Trial of Serum Treatment of Diphtheria." British Medical Journal 317 (October 31, 1998): 1243-1246.

MacKenzie, Debora. "Worming a Way In." New Scientist 161 (Jan. 30, 1999): 14.

Raju, Tonse N. K. "The Nobel Chronicles 1926: Johannes Andreas Grib Fibiger (1867-1928)." The Lancet 352 (November 14, 1998): 1635.

Stolley, P. D., Lasky, T. "Johannes Fibiger and His Nobel Prize for the Hypothesis That a Worm Causes Stomach Cancer." Annals of Internal Medicine 116 (1992): 765-769.

Weise, Allen B. "Barry Marshall and the Resurrection of Johannes Fibiger." Hospital Practice 31, no. 9 (Sept. 15, 1996): 105-113.

Other

Fibiger, Johannes. "Investigations on Spiropter carcinoma and the Experimental Induction of Cancer." Nobel Lecture, December 12, 1927. Reprinted in Nobel Lectures in Physiology or Medicine, vol. 2 (1922-1941). Amsterdam: Elsevier, 1965: 122-152.

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