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

Florey, Howard Walter (1898-1968)

English pathologist

The work of Howard Walter Florey gave the world one of its most valuable disease-fighting drugs, penicillin . Alexander Fleming discovered, in 1929, the mold that produced an antibacterial substance, but was unable to isolate it. Nearly a decade later, Florey and his colleague, biochemist Ernst Chain , set out to isolate the active ingredient in Fleming's mold and then conduct the clinical tests that demonstrated penicillin's remarkable therapeutic value. Florey and Chain reported the initial success of their clinical trials in 1940, and the drug's value was quickly recognized. In 1945, Florey shared the Nobel Prize in medicine or physiology with Fleming and Chain.

Howard Walter Florey was born in Adelaide, Australia. He was one of three children and the only son born to Joseph Florey, a boot manufacturer, and Bertha Mary Wadham Florey, Joseph's second wife. Florey expressed an interest in science early in life. Rather than follow his father's career path, he decided to pursue a degree in medicine. Scholarships afforded him an education at St. Peter's Collegiate School and Adelaide University, the latter of which awarded him a Bachelor of Science degree in 1921. An impressive academic career earned Florey a Rhodes scholarship to Oxford University in England. There he enrolled in Magdalen College in January 1922. His academic prowess continued at Oxford, where he became an excellent student of physiology under the tutelage of renowned neurophysiologist Sir Charles Scott Sherrington. Placing first in his class in the physiology examination, he was appointed to a teaching position by Sherrington in 1923.

Florey's education continued at Cambridge University as a John Lucas Walker Student. Already fortunate enough to have learned under a master such as Sherrington, he now came under the influence of Sir Frederick Gowland Hopkins, who taught Florey the importance of studying biochemical reactions in cells. A Rockefeller Traveling Scholarship sent Florey to the United States in 1925, to work with physiologist Alfred Newton Richards at the University of Pennsylvania, a collaboration that would later prove beneficial to Florey's own research. On his return to England and Cambridge in 1926, Florey received a research fellowship in pathology at London Hospital. That same year, he married Mary Ethel Hayter Reed, an Australian whom he'd met during medical school at Adelaide University. The couple eventually had two children.

Florey received his Ph.D. from Cambridge in 1927, and remained there as Huddersfield Lecturer in Special Pathology. Equipped with a firm background in physiology, he was now in a position to pursue experimental research using an approach new to the field of pathology. Instead of describing diseased tissues and organs, Florey applied physiologic concepts to the study of healthy biological systems as a means of better recognizing the nature of disease. It was during this period in which Florey first became familiar with the work of Alexander Fleming. His own work on mucus secretion led him to investigate the intestine's resistance to bacterial infection . As he became more engrossed in antibacterial substances, Florey came across Fleming's report of 1921 describing the enzyme lysozyme, which possessed antibacterial properties. The enzyme, found in the tears, nasal secretions, and saliva of humans, piqued Florey's interest, and convinced him that collaboration with a chemist would benefit his research. His work with lysozyme showed that extracts from natural substances, such as plants, fungi and certain types of bacteria , had the ability to destroy harmful bacteria.

Florey left Cambridge in 1931 to become professor of pathology at the University of Sheffield, returning to Oxford in 1935 as director of the new Sir William Dunn School of Pathology. There, at the recommendation of Hopkins, his productive collaboration began with the German biochemist Ernst Chain. Florey remained interested in antibacterial substances even as he expanded his research projects into new areas, such as cancer studies. During the mid 1930s, sulfonamides, or sulfa drugs , had been introduced as clinically effective against streptococcal infections, an announcement which boosted Florey's interest in the field. At Florey's suggestion, Chain undertook biochemical studies of lysozyme. He read much of the scientific literature on antibacterial substances, including Fleming's 1929 report on the antibacterial properties of a substance extracted from a Penicillium mold, which he called penicillin. Chain discovered that lysozyme acted against certain bacteria by catalyzing the breakdown of polysaccharides in them, and thought that penicillin might also be an enzyme with the ability to disrupt some bacterial component. Chain and Florey began to study this hypothesis, with Chain concentrating on isolating and characterizing the enzyme, and Florey studying its biological properties.

To his surprise, Chain discovered that penicillin was not a protein, therefore it could not be an enzyme. His challenge now was to determine the chemical nature of penicillin, made all the more difficult because it was so unstable in the laboratory. It was, in part, for this very reason that Fleming eventually abandoned a focused pursuit of the active ingredient in Penicillium mold. Eventually, work by Chain and others led to a protocol for keeping penicillin stable in solution. By the end of 1938, Florey began to seek funds to support more vigorous research into penicillin. He was becoming convinced that this antibacterial substance could have great practical clinical value. Florey was successful in obtaining two major grants, one from the Medical Research Council in England, the other from the Rockefeller Foundation in the United States.

By March of 1940, Chain had finally isolated about one hundred milligrams of penicillin from broth cultures. Employing a freeze-drying technique, he extracted the yellowish-brown powder in a form that was yet only ten percent pure. It was non-toxic when injected into mice and retained antibacterial properties against many different pathogens. In May of 1940, Florey conducted an important experiment to test this promising new drug. He infected eight mice with lethal doses of streptococci bacteria, then treated four of them with penicillin. The following day, the four untreated mice were dead, while three of the four mice treated with penicillin had survived. Though one of the mice that had been given a smaller dose died two days later, Florey showed that penicillin had excellent prospects, and began additional tests. In 1941, enough penicillin had been produced to run the first clinical trial on humans. Patients suffering from severe staphylococcal and streptococcal infections recovered at a remarkable rate, bearing out the earlier success of the drugs in animals. At the outset of World War II, however, the facilities needed to produce large quantities of penicillin were not available. Florey went to the United States where, with the help of his former colleague, Alfred Richards, he was able to arrange for a U.S. government lab to begin large-scale penicillin production. By 1943, penicillin was being used to treat infections suffered by wounded soldiers on the battlefront.

Recognition for Florey's work came quickly. In 1942, he was elected a fellow in the prestigious British scientific organization, the Royal Society, even before the importance of penicillin was fully realized. Two years later, Florey was knighted. In 1945, Florey, Chain and Fleming shared the Nobel Prize in medicine or physiology for the discovery of penicillin.

Penicillin prevents bacteria from synthesizing intact cell walls. Without the rigid, protective cell wall, a bacterium usually bursts and dies. Penicillin does not kill resting bacteria, only prevents their proliferation. Penicillin is active against many of the gram positive and a few gram negative bacteria. (The gram negative/positive designation refers to a staining technique used in identification of microbes.) Penicillin has been used in the treatment of pneumonia , meningitis , many throat and ear infections, Scarlet Fever, endocarditis (heart infection), gonorrhea , and syphilis .

Following his work with penicillin, Florey retained an interest in antibacterial substances, including the cephalosporins, a group of drugs that produced effects similar to penicillin. He also returned to his study of capillaries, which he had begun under Sherrington, but would now be aided by the recently developed electron microscope . Florey remained interested in Australia, as well. In 1944, the prime minister of Australia asked Florey to conduct a review of the country's medical research. During his trip, Florey found laboratories and research facilities to be far below the quality he expected. The trip inspired efforts to establish graduate-level research programs at the Australian National University. For a while, it looked as if Florey might even return to Australia to head a new medical institute at the University. That never occurred, although Florey did do much to help plan the institute and recruit scientists to it. During the late 1940s and 1950s, Florey made trips almost every year to Australia to provide consultation to the new Australian National University, to which he was appointed Chancellor in 1965.

Florey's stature as a scientist earned him many honors in addition to the Nobel Prize. In 1960, he became president of the Royal Society, a position he held until 1965. Tapping his experience as an administrator, Florey invigorated this prestigious scientific organization by boosting its membership and increasing its role in society. In 1962, he was elected Provost of Queen's College, Oxford University, the first scientist to hold that position. He accepted the presidency of the British Family Planning Association in 1965, and used the post to promote more research on contraception and the legalization of abortion. That same year, he was granted a peerage, becoming Baron Florey of Adelaide and Marston.

See also Bacteria and bacterial infection; History of the development of antibiotics; Infection and resistance

Howard Walter Florey

The Australian experimental pathologist and teacher Howard Walter Florey, Baron Florey of Adelaide (1898-1968), helped isolate penicillin and develop it as a successful nontoxic antibacterial agent for use in medical treatment.

Howard W. Florey, the son of Joseph Florey, was born on Sept. 24, 1898, at Adelaide. After attending St. Peter's Collegiate School and Adelaide University (1916-1921), where he received a degree in medicine, he entered Magdalen College, Oxford, as a Rhodes scholar in 1921 and then Cambridge University in 1924. During 1925-1926 he was Rockefeller traveling fellow in the United States. In 1926 he was appointed Freedom research fellow at Cambridge. In the same year he married Mary Ethel Reed; they had two children.

Florey became successively Huddersfield lecturer in special pathology at Cambridge University in 1927, Joseph Hunter professor of pathology at the University of Sheffield in 1931, and professor and head of the Sir William Dunn School of Pathology at Oxford University in 1935, a position which he held until 1962, when he resigned to become provost of Queen's College, Oxford. In 1935 he invited the chemist Ernst B. Chain to Oxford to direct the work of the biochemistry department. After numerous vicissitudes Florey and Chain succeeded (1940-1941) in isolating the drug penicillin in completely purified form, which turned out to be a million times more active than the crude substance first observed in 1928 by Alexander Fleming. Penicillin is usually measured in Oxford units, also called Florey units. In 1941 the Rockefeller Foundation brought Florey to the United States to persuade American authorities of the need to make major facilities available for the rapid development of penicillin production. His journey was eminently successful, and by the last stages of World War II large amounts of penicillin were in clinical use.

The research interests of Florey were wide-ranging, and he remained an active laboratory investigator all his life. Throughout his career he was preoccupied with the structure and function of the smaller blood vessels and their relation to the movement of lymph and cells in inflammation. His work on lysozyme led to his general study of antibiotics in collaboration with Chain. In temperament Florey was reserved but sure of himself. He was above all a skilled experimentalist with little liking for speculation.

Florey was the recipient of numerous prizes, honors, and honorary degrees, including the Nobel Prize in physiology or medicine in 1945; he was created a baron in 1965. In 1944 he became Nuffield visiting professor to Australia and New Zealand. He was largely responsible for the detailed planning and policy of the John Curtin School of Medical Research of the Australian National University. In 1965 he became chancellor of this university. He died on Feb. 21, 1968.

Further Reading

Lloyd G. Stevenson, Nobel Prize Winners in Medicine and Physiology, 1901-1950 (1953), includes a sketch on Florey. Discussions of his life and work can also be found in John D. Ratcliff, Yellow Magic: The Story of Penicillin (1945); Laurence J. Ludovici, Fleming, Discoverer of Penicillin (1952); and André Maurois, The Life of Sir Alexander Fleming, Discoverer of Penicillin (1959; trans. 1959). □

Florey, Sir Howard Walter

Howard Walter Florey (1898-1968) was one of two men who developed penicillin, the first antibiotic. Florey was born in Australia and attended the University of Adelaide before winning a Rhodes Scholarship to study at Oxford University in England. In the 1920s and 1930s Florey's original research was in inflammatory reactions (such as allergic reactions) where the body produces mucus (a slimy secretion) to expel an irritating invader.

Working With Chain

In 1938, Florey began his work on antibacterial substances. He had hired Ernst Boris Chain (1906-1979) to work with him on these problems. Chain brought to Florey's attention Sir Alexander Fleming (1881-1955)'s writings on how molds (the origin of penicillin) had killed bacteria in one of his sample dishes. Florey and Chain then worked on synthesizing (artificially creating) a pure form of penicillin. The two researchers tested their conclusions on animals and humans with out-standing results.

After sharing the 1945 Nobel Prize in medicine with Chain and Fleming, Florey traveled to the United States to encourage production of penicillin for routine medical use. As a professor of pathology at Oxford, he also contributed to research on electron microscopy and circulatory and pulmonary (lung and breathing-related) illnesses.

Florey, Howard Walter, Baron (1898–1968) Australian pathologist, who moved to Oxford in 1922. After working in Cambridge and Sheffield (studying lysozyme), he returned to Oxford in 1935. There he teamed up with Ernst Chain and by 1939 they succeeded in isolating and purifying penicillin. They also developed a method of producing the drug in large quantities and carried out its first clinical trials. The two men shared the 1945 Nobel Prize for physiology or medicine with penicillin's discoverer, Alexander Fleming.