Fildes, Paul Gordon
FILDES, PAUL GORDON
(b. London, England, 10 February 1882; d. London, 5 February 1971)
The son of Sir Luke Fildes, an illustrator and portrait painter, and of Fanny Woods, Fildes attended Margate Preparatory School and Winchester College before entering Trinity College, Cambridge, in 1900. Upon graduation in 1904, Fildes entered London Hospital Medical College, where he worked with William Bulloch in the Department of Bacteriology and received his medical degree in 1909. Subsequently he received honorary degrees from the University of Cambridge (1948) and the University of Reading (1959). For his contributions to the war effort he was awarded the military O.B.E. in 1919 and was knighted in 1946. His scientific awards included election as a fellow of the Royal Society in 1934, its Royal Medal in 1953, and its Copley Medal in 1963. In 1950 Fildes gave the first Leeuwenhoek Lecture of the Royal Society. With James McIntosh, J. A. Murray, and W. E. Gye, in 1920 he founded the British Journal of Experimental Pathology; he served as general editor for many years.
After receiving his degree, Fildes continued to serve as assistant to Bulloch at London Hospital. Between 1909 and 1914, together with James McIntosh, he undertook an investigation of syphilis, about which knowledge was rapidly expanding. They began with a carefully controlled study that demonstrated the effectiveness of Salvarsan (606) in the treatment of syphilis. Salvarsan (606), or arsphenamine, an organic arsenic compound, was developed by Paul Ehrlich and introduced for clinical trials in 1910. Almost immediately controversy arose, in part because of high demand and in part owing to questions about the effectiveness and safety of the drug. In response to questions about the effectiveness of Salvarsan (606), Fildes traced part of the problem to a lack of standardization in the procedures for the Wasserman test and himself developed a standardized procedure. Salvarsan (606) was also alleged to produce a toxic reaction, which Fildes and McIntosh traced not to the drug but to the saline solution used to reconstitute it. This discovery led to the generalized use of “pyrogen-free” distilled water for reconstituting drugs and vaccines.
During World War I, Fildes’ attention was directed to problems resulting from battle wounds. Fildes developed a spray of malachite green and mercuric chloride that was very successful in treating deep infected wounds. Also during the war Fildes and McIntosh investigated gangrene and traced it to an anaerobic bacterium. It was then very difficult to study anaerobes, so they designed a special oxygen-free jar with which they investigated several anaerobes isolated from war wounds.
Fildes is best known for his work on bacterial nutrition, research that began between 1918 and 1924 with a study of influenza undertaken with Mcintosh. In the course of this work, Fildes showed that two factors from blood, which he labeled X and V, were necessary for the growth of Haemophilus influenzae. He proceeded to classify hemoglobulinophilic bacteria by whether they required just one of these factors or both. The X factor was identified as hematin, and in 1936 the V factor was identified by Andre Lwoff as Otto Warburg’s coenzyme I, nicotinamide adenine dinucleotide. In subsequent work on nutritional requirements of bacteria, Fildes established that several bacteria required tryptophan as a nutrient, and that other bacteria which greq without tryptophan, synthesized it. He interpreted this as showing that tryptophan is an essential component of bacterial protoplasm (he later coined the term essential metabolite for such substances)and argued that when the bacterium could not synthesize it, it had to be supplied as a nutrient.
Through this work Fildes was led to develop connections between microbiology and chemistry, and sought the cooperation of the biochemist H. D. Kay. Another project during the late 1920’s led Fildes to recognize the potential for employing techniques developed in physical chemistry, especially William Mansfield Clark’s use of indicator dyes for determining the oxidation-reduction potential of various media, in studying metabolic phenomena. Fildes recognized the need for using these techniques in the course of studying why Clostridium tetani did not grow in healthy tissues. After developing evidence that refuted the claim that the tetanus bacillus failed to grow because it was destroyed by phagocytes, Fildes proposed that it succumbed when overoxygenated. Fildes pursued this idea using Clark’s redox dyes and established a threshold potential required for germination of tetanus spores. The use of Clark’s dye technique proved too laborious for generalized use, and to continue this work Clark began to collaborate with the physical chemist Bert Knight, who developed a glass electrode technique for measuring and regulating oxidationreduction potentials.
Having come to appreciate the potential for cooperative research involving bacteriology and chemistry, Fildes proposed the establishment of an interdisciplinary research laboratory staffed by bacteriologists and chemists. With funding from the Medical Research Council, the Leverhulme Trustees, and the Halley Stuart Trust Fund, the Medical Research Council Unit in Bacterial Chemistry was created in 1934 at the Bland Sutton Institute of Pathology of Middlesex Hospital. This group continued Fildes’ early investigations on the nutritional requirements of bacteria, establishing the amino acid and B vitamin requirements for several (for instance, nicotinamide for Proteus vulgaris and glutamine for Streptococcus hemolyticus).
While Fildes’ work illuminated bacterial nutrition requirements and metabolic processes, his interest remained that of a bacteriologist. He studied how to control the growth and the production of toxins by bacteria. He was responsible for an important advance in this area when he made a connection with work on antibacterial drugs. Sir Lionel Whitby’s laboratory at the Bland Sutton Institute was investigating the antibacterial action of sulfonamide. It was proposed that such an antibacterial substance might function by competing with essential metabolites. Fildes’suggestion that sulfonamide might compete with glutamine was not supported; but subsequently Daniel D. Woods, working in Fildes’ laboratory, showed that the naturally occurring compound p-aminobenzoic acid could compete with and reverse the effects of sulfonamide. Woods and Fildes surmised that p-aminobenzoic acid was an essential metabolite and soon confirmed this suggestion. This provided the basis for the Woods Fildes hypothesis that chemotherapeutic agents can operate by competing with essential metabolites.
The work of the research institute was interrupted by World War II, during which time Fildes moved to the Chemical Warfare Experimental Station at Porton. There he played an instrumental role in developing Britain’s germ warfare effort and in getting the United States to develop its own effort. After the war Fildes reconstituted the Medical Research Council Unit in Bacterial Chemistry at the Lister Institute. His own work at the new location focused on the tryptophan requirements of bacteria and on possible tryptophan analogues that might serve as chemotherapeutic agents. After his retirement from the Medical Research Council unit in 1949, Fildes moved to a laboratory in the Sir William Dunn School of Pathology at Oxford, where, for thirteen years, he investigated the interaction of viruses with bacterial hosts by carefully controlling environmental factors. In one of these investigations he examined the effect of tryptophan on the adsorption of a virus to bacterial cells.
Fildes pioneered in the integration of biochemical studies with microbiology. Working from the biochemical side, Marjorie Stephenson was another contributor to the development of a systematic study of bacterial enzymes and metabolism, but among bacteriologists Fildes was unique during his time in recognizing the importance of biochemical studies in developing an understanding of the physiology and function of bacteria.
1. Original Works. Among Fildes’ most important writings are Syphilis from the Modern Standpoint (London 1911), written with James Mcintosh; “A New Antiseptic Mixture for the Treatment of Gunshot Wounds and General Surgical Application,” in Lancet (1915), 2 , 165–170, written with L. W. Rajchman and G. L. Cheatle; “The Aetiology of Influenza,” in British Journal of Experimental Pathology, 1 (1920), 119–126, 159–174, written with James Mcintosh; “The Growth Requirements of Haemolytic Influenza Bacilli and the Bearing of These upon the Classification of Related Organisms,” ibid., 5 (1924), 69–74; “Tetanus VI. The Conditions Under Which Tetanus Spores Germinate in Vivo,” ibid., 8 (1927), 387–393; “Tetanus VIII. The Positive Limit of Oxidation-Reduction Potential Required for the Germination of Spores of B, tetani in vitro.,” ibid., 10 (1929), 197–204; “Oxidation-Reduction Studies in Relation to Bacterial Growth. III. The Positive Limit of Oxidation-Reduction Potential Required for the Germination of B, tetani Spores in Vitro, ’ in Biochemical Journal, 24 (1930), 1496–1502, written with B.C.J.G. Knight; “The Nitrogen and Vitamin Requirements of B. typhosus, ’ in British Journal of Experimental Pathology, 14 (1933), 189–196, written with G.P. Gladstone and B.C.J.G. Knight; “Tryptophan and the Growth of Bacteria,” ibid., 343–349, written with B.C.J.G. knight: “Some Medical and Other Aspects of Bacterial Chemistry. President’s Address,” in Proceedings of the Royal Society of medicine, 28 (1934), 79–90; “Inhibition of Bacterial Growth by Indoleacrylic Acid and Its Relation to Tryptophan: An Illustration of the Inhibitory Action of Substances Chemically Related to an Essential Metabolite,” in British Journal of Experimental Pathology, 22 (1941), 293–298; “The Evolution of Microbiology. Leeuwenhoek Lecture,” in Proceedings of the Royal Society of London, B138 (1951), 65–74; and “Tryptophan as a Bacteriophage Adsorption Factor,” in British Journal of Experimental Pathology, 38 (1957), 563–572, written with D.Kay.
II Secondary Literature. On Fildes’ life and career, see G. P. Gladstone, B. C. J. G. Knight, and Sir Graham Wilson, “Paul Gordon Fildes,” in Biographical Memoirs of Fellows of the Royal Society, 19 (1973), 317–347; and Robert Kohler, “Bacteriological Physiology: The Medical Context,” in Bulletin of the history of Medicine, 59 (1985), 54–74.