Florey, Howard Walter

Florey, Howard Walter

(b. Adelaide, Australia, 24 September 1898; d. Oxford, England, 21 February 1968)

pathology.

Florey’s scientific career was devoted to the experimental study of disease processes. His most notable contribution to science was the development of penicillin as a systemic antibacterial antibiotic suitable for use in man.

Florey was the third and last child, and the only son, of Joseph Florey and his second wife, Bertha Mary Wadham, a native of Australia. Joseph Florey owned a boot factory, and the family was in comfortable circumstances. The son attended St. Peter’s Collegiate School, Adelaide, as a day boy. He had a brilliant scholastic career, obtaining scholarships at St. Peter’s and subsequently for study at the University of Adelaide.

From an early age Florey had decided to study medicine and carry out medical research, rather than learn the management of the family business. He enrolled in the Faculty of Medicine at the University of Adelaide in 1917 and graduated M.B., B.S. five years later. Receipt of the Rhodes Scholarship for South Australia in 1922 enabled him to go to Oxford, where he studied in the Honours Physiology School. His exposure there to the great neurophysiologist Sir Charles Sherrington profoundly affected his outlook on pathology. He was so impressed by the value for aspiring young pathologists of the physiological and biochemical outlook conferred by the Honours Physiology School that when he later became professor of pathology at Oxford, he insisted that all candidates for the Ph.D. should study at the Honours School before beginning experimental work in the Sir William Dunn School. From Oxford, Florey went to Cambridge for a year and then spent a year in the United States as a Rockefeller Foundation traveling fellow. After a short period at the London Hospital he returned to Cambridge, where he took the Ph.D. degree. The most important formative influence at Cambridge came not from the department of pathology but from the biochemist Sir Frederic Gowland Hopkins, then at the height of his career.

In 1926 Florey married Mary Ethel Reed, who had been a fellow medical student at the University of Adelaide; they had a son, Charles, and a daughter, Paquita. Mrs. Florey died in 1966, and in 1967 he married the Hon. Margaret Jennings, a former colleague in his Oxford laboratories.

In 1931 Florey was appointed Joseph Hunter professor of pathology at the University of Sheffield. Four years later he moved to Oxford as professor in charge of the Sir William Dunn School of Pathology; Sir Edward Mellanby played an important part in this appointment. It was a milestone in the history of pathology in Britain, because for the first time a man trained in experimental physiology and viewing pathology with a physiologist’s eye came into a position of influence in the teaching of the subject. Florey remained professor of pathology at Oxford from 1935 until 1962, when he resigned to become provost of Queen’s College, Oxford.

Florey created a very lively and stimulating atmosphere at Oxford, which led to close contacts between department members, who had been selected to cover a wide range of scientific disciplines. Not only was this spirit of collaboration all-important in the early work on penicillin, but it also resulted in the Sir William Dunn School’s becoming the leading center of experimental pathology in Europe, through which a succession of able and brilliant young men passed.

Although he remained in Britain after 1922, with a life centered at Oxford after 1935, Florey remained Australian in accent and outlook. In 1944 he was invited to Australia by the prime minister, John Curtin, to report on the Australian situation in medical research. His report led to the establishment of the Australian National University as a graduate university in 1946. Florey was very closely connected with this university for the next decade, as a senior adviser with a particular interest in the John Curtin School of Medical Research. He played the major role in establishing this school, and he visited the Australian National University for consultation almost every year until 1957. In 1965 he was appointed chancellor of the university and resumed his annual visits to Canberra.

The influence of both Sherrington and Hopkins can be traced throughout Florey’s career. He was exceptional among contemporary pathologists in the United Kingdom in that he was interested in the study, by physiological and biochemical methods, of the functional changes of cells which lead to pathological changes, rather than merely in the morphological description of diseased tissues. He also had the pathologist’s interest in structure, and in the latter part of his life he made extensive use of electron microscopy to study structure with the greater detail and precision made possible by that instrument. His basic tools were physiological operative techniques, in the use of which he displayed superb skill and ingenuity.

The idea of antibiosis, or microbial antagonism, was not new in Florey’s time; Pasteur had made observations on the topic. Neither was penicillin new; Sir Alexander Fleming had discovered it in 1929, although he had looked on it only as a useful antiseptic for local application and had not realized that it was in fact a potent systemic antibacterial substance. Florey and his colleague E. B. Chain transformed what was a bacteriological curiosity into a clinical tool of immense value, and in so doing they opened up the new industry of antibiotic production. In the context of man’s cultural evolution, it is interesting to reflect that the utilization of molds for the production of antibiotics represented the first important domestication of a species since prehistoric times.

Shortly after he arrived at Oxford, Florey sought Hopkins’ advice on a suitable person to lead a biochemical unit in the Dunn School of Pathology. Hopkins recommended E. B. Chain, a young refugee from Nazi Germany then in Hopkins’ laboratory, and Chain moved to Oxford in 1935. This was a critically important development as far as penicillin was concerned, for Chain had the biochemical insight that enabled him to purify penicillin without loss of its potency—a feat that had eluded Harold Raistrick, who had attempted this a decade earlier on behalf of Fleming.

Florey had long had an interest in natural antibacterial substances, and in 1930 he began a study of the antibacterial properties of lysozyme, an enzyme discovered by Fleming in 1921. This work was pursued until the enzyme was purified and the nature of its substrate determined.¹ It was against this background that Florey and Chain, in 1938–1939, initiated a systematic investigation of the biological and chemical properties of the antibacterial substances produced by bacteria and molds. As they recorded in the first publication on penicillin (1940) and in their major book on the subject, Antibiotics (1949), they were greatly encouraged by the success of Rene Dubos and his colleagues in isolating tyrothricin from the soil bacterium Bacillus brevis and in purifying its component antibiotic polypeptides, tyrocidin and gramicidin (only to find that although they were effective antibacterial agents, they were too toxic for systemic use).²

Florey emphasized that his research on antibacterial agents had been conceived as an academic study with possibilities of wide theoretical interest, not as “war work.” By good fortune, and with excellent scientific judgment, Florey and Chain selected Fleming’s penicillin as the first substance to be studied in detail. It proved so promising experimentally in mice with streptococci, staphylococci, and gas gangrene organisms (showing true systemic antibacterial potency combined with minimum toxicity) that all the resources of the Oxford laboratory were turned to its production on a scale that would allow clinical trials to be carried out. Many investigations, involving workers in several scientific disciplines, were necessary before penicillin could be used in human medicine. Because of the variety of skills possessed by the scientists Florey had gathered around him, developmental work proceeded rapidly. A simple and effective assay system was devised, the antibacterial spectrum of penicillin was determined, and pharmacological and toxicological studies were made in mice and later in man. In spite of efforts to increase the yield from the cultures of Penicillium notatum, it was necessary to process 2,000 liters of culture fluid to obtain enough penicillin to treat a single case of sepsis in man. In order to scale up production very unusual equipment was used, such as enameled bedpans for culture vessels; the “factory” on South Parks Road, Oxford, was far removed from the vast fermentation tanks and sophisticated chemical engineering of the modern antibiotics industry.

In 1941 penicillin was used in treating nine cases of human bacterial infection. All responded dramatically. The next stage called for other skills, at which Florey proved to be as adept as he had been in the laboratory. Industry in wartime Britain could not be expected to produce supplies of penicillin in the amounts so urgently needed, so Florey and his colleague Norman Heatley went to the United States (which had not yet entered World War II) to stimulate interest in its production there. The chairman of the Committee on Medical Research, Office of Scientific Research and Development, was the pharmacologist A. N. Richards, with whom Florey had worked as a Rockefeller. Foundation traveling fellow in 1929–1930. Florey’s enterprise and Richards’ perspicacity were responsible for the production of penicillin in sufficient quantities for the treatment of war casualties in 1944.³ Florey journeyed widely to investigate the use of penicillin in the field, traveling to North Africa in 1943 and subsequently to the Soviet Union.

Having acquired such skill in antibiotic research, it was natural that Florey should continue it in the Oxford laboratories well after the end of World War II. The most successful outcome was the development of cephalosporin C. Florey played a part in the early work on the cephalosporins, but later developments were the work of his colleague E. P. Abraham.⁴

After about 1955 Florey returned to research in experimental pathology. His interests ranged widely but showed a continuing preoccupation with the structure and function of the smaller blood vessels and their relation to the movement of lymph and cells in the process of inflammation. In his studies on capillary function and cell migration he could fully indulge his interest in the fine structure of cells and tissues, his pleasure in skilled manipulation, and his enthusiasm for photography. These interests were manifested in his use of the rabbit-ear chamber and other techniques for in vivo microscopy, and later of the electron microscope.

The physiology of mucus secretion was another area in which Florey did valuable work, particularly in clarifying its protective function in the respiratory and intestinal tracts. His early recognition of the hormonal control of the secretion of Brunner’s glands has recently been confirmed; while a third thread that runs through Florey’s work was an interest in human reproduction, initially at the experimental level, where he was interested in the movement of spermatozoa in the female genital tract.

Florey remained an active laboratory investigator all his life. After penicillin, the main topics with which he was concerned were the relatively insoluble antibiotic micrococcin, the electron microscopy of blood vessels, and the nature of atherosclerosis; he published two major works on the structure and function of endothelial cells of blood vessels in 1967, the year before his death.

Florey’s other great contribution to science was as president of the Royal Society (1960–1965), the highest office in British science. He was the first Australian and the first pathologist to hold that post. During his tenure, he established the Royal Society Population Study Group and acted as its chairman until the time of his death.

His work was recognized by numerous honors, both public and academic: many honorary degrees from British and Australian universities; the Nobel Prize for physiology or medicine (1945), which Florey shared with Fleming and Chain; the Lister Medal of the Royal College of Surgeons (1945); the Copley Medal of the Royal Society (1957); and the Lomonosov Medal of the Soviet Academy of Sciences (1965).

Florey was elected a fellow of the Royal College of Physicians in 1951, corresponding member of the Australian Academy of Science in 1958, fellow of the Postgraduate Medical Foundation of Australia in 1965, foreign member of the American Philosophical Society in 1963, foreign associate of the National Academy of Sciences of the United States (1963), and foreign honorary member of the American Academy of Arts and Sciences (1964). He was created knight in 1944 and commander of the Legion of Honor in 1946; in 1965 he received the O.M. and was created a life peer, Baron Florey of Adelaide and Marston.

In temperament Florey was reserved but sure of himself. His chief characteristics were his common sense and his intense sense of obligation toward, and responsibility for, his scientific colleagues. He had no liking for speculation: for Florey an idea was not worth having unless it could be used to help design an experiment which would, or could in principle, give a definitive result. Perhaps this is what made him one of the most effective medical scientists of his generation.

NOTES

1. L. A. Epstein and E. Chain, “Some Observations on the Preparation and Properties of the Substrate of Lysozyme,” in British Journal of Experimental Pathology, 21 (1940), 339–355.

2. R. J. Dubos, “Studies on a Bactericidal Agent Extracted From a Soil Bacillus. I. Preparation of the Agent. Its Activity in vitro,” in Journal of Experimental Medicine, 70 (1939), 1–17; R. D. Hotchkiss and R. J. Dubos, “Fractionation of the Bactericidal Agent From Cultures of a Soil Bacillus,” in Journal of Biological Chemistry, 132 (1940), 791–792; and “Chemical Properties of Bactericidal Substances Isolated From Cultures of a Soil Bacillus,” ibid., 793–794.

3. See “Alfred Newton Richards, Scientist and Man,” in Annals of Internal Medicine, 71 (1969), supp. 8, 56; supp. 9, 63–64.

4. E. P. Abraham and G. G. F. Newton, “New Penicillins, Cephalosporin C, and Penicillinase,” in Endeavour, 20 (1961), 92–100.

BIBLIOGRAPHY

Florey’s works include “The Secretion of Mucus by the Colon,” in British Journal of Experimental Pathology, 11 (1930), 348–361; “Some Properties of Mucus, With Special Reference to Its Antibacterial Functions,” ibid., 192–208, written with N. E. Goldsworthy: “Penicillin as a Chemotherapeutic Agent,” in Lancet (1940), 2 , 226–228, written with E. Chain et al.; “Further Observations on Penicillin,” ibid. (1941), 2 , 177–188, written with E. P. Abraham, E. Chain, et al.; Antibiotics: A Survey of Penicillin, Streptomycin and Other Antimicrobial Substances From Fungi, Actinomycetes, Bacteria and Plants, 2 vols. (London, 1949), written with E. Chain et al. ; and his eds. of General Pathology (London, 1954, 1958, 1962, 1970).

A complete bibliography will be found in the memoir on Florey in Biographical Memoirs of Fellows of the Royal Society (1971).

Frank Fenner