Few people know that in parallel with the race to produce a bomb that would kill people by the hundred thousand, scientists in England ran another race, a race to produce a drug that was to save the lives of millions. The book under review is the story of Alexander Fleming, the laconic Scotsman whose chance discovery set the race in motion. While working as a bacteriologist at a London hospital in 1928, Fleming found that a culture plate seeded with staphylococci had become contaminated with a mold. Instead of discarding it, as others might have done, he noticed something unusual: colonies of these bacteria had grown everywhere except near the mold, where he saw a clear patch. He now cultured the mold and discovered that the broth filtered from it stopped the growth of several kinds of deadly bacteria. Publication of his discovery in a scientific journal stirred up hardly a ripple, and he did little more about it.
Nine years later Ernst Chain, a young German biochemist at Oxford, came across Fleming’s paper and decided together with his professor, the Australian pathologist Howard Florey, to find out the nature of the active substance in Fleming’s broth and the way it stops the growth of bacteria. With herculean labor, Chain and several of his colleagues extracted a minute quantity of what they believed to be the pure substance from gallons of broth and gave it to Florey to test.
In May 1940, while the defeated British Army was being evacuated from France, Howard Florey and his team achieved a brilliant victory. Florey had injected lethal numbers of streptococci, the kind of bacteria that causes blood poisoning, meningitis, and puerperal fever, into eight mice. He then injected the mold extract into four of them and left the other four untreated; the treated mice remained healthy and the untreated ones were dead the next day. These were the first steps in the purification of penicillin and the realization of its unparalleled therapeutic powers. As a result Fleming became a world hero, while Florey, Chain, and their colleagues’ names have remained unknown outside the world of science.
Macfarlane has written a scientific thriller tracing the almost unbelievable combination of events that guided Fleming to his discovery. He then shows why no one, not even Fleming himself, recognized the importance of his discovery and why Fleming, even though he had abandoned it to others, reaped nearly all the fame. Macfarlane’s book is the companion volume to his earlier, brilliant biography of Howard Florey,1 and is equally enthralling.
Fleming was graduated as a physician at London University in 1906 and became junior assistant in Sir Almroth Wright’s Inoculation Department of St. Mary’s Hospital in London. His later specialization in bacteriology was brought about by World War I when Wright and his assistants were posted to a grim military hospital in Boulogne. Here Fleming found that the antiseptics like carbolic acid, then commonly used for the treatment of open wounds, killed the white blood cells that constitute the body’s own defense and let the bacteria that had buried themselves in the tissues survive. According to Macfarlane, this experience made him aware of the need for an antiseptic that penetrates the wounds and leaves the beneficial white blood cells alive.
In 1921, Fleming made the first of the two observations that were to change medical history. Fleming’s notebooks, now at the British Museum, fail to describe how it happened; Macfarlane therefore quotes the account of an eyewitness at St. Mary’s Hospital, where Fleming worked in the innoculation department.
Early on, Fleming began to tease me about my excessive tidiness in the laboratory. At the end of each day’s work I cleaned my bench, put it in order for the next day and discarded tubes and culture plates for which I had no further use. He, for his part, kept his cultures…for two or three weeks until his bench was overcrowded with 40 or 50 cultures. He would then discard them, first of all looking at them individually to see whether anything interesting or unusual had developed. I took his teasing in the spirit in which it was given. However, the sequel was to prove how right he was, for if he had been as tidy as he thought I was, he would never have made his two great discoveries—lysozyme and penicillin.
Discarding his cultures one evening, he examined one for some time, showed it to me and said “This is interesting.” The plate was one on which he had cultured mucus from his nose some two weeks earlier, when suffering from a cold. The plate was covered with golden-yellow colonies of bacteria, obviously harmless contaminants deriving from the air or dust of the laboratory, or blown in through the window from the air in Praed Street. The remarkable feature of this plate was that in the vicinity of the blob of nasal mucus there were no bacteria; further away another zone in which the bacteria had grown but had become translucent, glassy and lifeless in appearance; beyond this again were the fully grown, typical opaque colonies. Obviously something had diffused from the nasal mucus to prevent the germs from growing near the mucus, and beyond this zone to kill and dissolve bacteria already grown.
Fleming found that saliva, tears, and the white of eggs also dissolved the bacteria, and that these fluids did no harm to white blood cells, which made him wonder if animals themselves manufacture the ideal antiseptic for which everyone had been searching. This proved a false hope, because Fleming soon found that his nasal mucus or tears left the common disease-producing bacteria unharmed; the bacteria that had dissolved proved to be of a unique kind, blown into his room from no one knew where. A classical scholar named them Micrococcus lysodeikticus and the unknown agent in Fleming’s nose “lysozyme.” Fleming continued to work on it for many years in the hope that it might prove of therapeutic value, even after his discovery of penicillin, but not knowing biochemistry, he never found out what it was or how it worked. This omission was to prove crucial for later developments. Lysozyme was later found, not by Fleming, but by Ernst Chain—who was to be one of the other chief actors in the penicillin drama—to be an enzyme that acts by dissolving the membranes of invading bacteria.
If the discovery of lysozyme was made possible only by the adventitious landing on Fleming’s bench of a rare and hitherto unknown germ, his discovery of penicillin in 1928 was due to a combination of circumstances improbable beyond belief, of which Fleming’s own terse description in the British Journal of Experimental Pathology in 1929 provides no hint:
While working with staphylococcus variants, a number of culture-plates were set aside on the laboratory bench and examined from time to time. In the examinations these plates were necessarily exposed to the air and they became contaminated with various micro-organisms. It was noticed that around a large colony of a contaminating mould the staphylococcus colonies became transparent and were obviously undergoing lysis [i.e., being broken up].
Bacteriologists normally grow microorganisms by cooking a nutrient broth, pouring it on a round dish four inches wide, letting it solidify into a jelly, stabbing the jelly many times over with a platinum wire dipped into an earlier culture of the microorganism, and finally heating the dish for a day or so in an incubator kept at body temperature.
Many years after the event, Ronald Hare, who had been assistant in the inoculation department at the time, tried to rediscover penicillin by preparing a culture plate seeded with staphylococci in just this way and then contaminating it with Fleming’s mold.2 The mold had no effect! To produce the clear patch that Fleming had found, Hare had to seed the dish with the molds before the staphylococci, but there he encountered another difficulty: the molds would not grow at body temperature. So what could have happened?
In 1928 Fleming was asked to write a chapter on staphylococci for a handbook, and for this purpose tried to reproduce some anomalous strains reported in the literature; he was helped by a student, D.M. Pryce. As I have said, Fleming tended to prepare many bacterial cultures and leave them scattered on his bench. Pryce told Hare that before going on vacation, Fleming had pushed all those cultures together into a corner to give Pryce space to work in. Pryce himself later went on vacation with Hare, and Fleming returned before they did. When Pryce came back Fleming had piled up his cultures on a tray of antiseptic. Fleming picked up some of them and showed them to Pryce, who remembers that “he took one plate up, looked at it, and after a while said ‘That’s funny.’ ” That was the now famous plate referred to in the opening paragraph of Fleming’s paper.
To explain what happened, Hare excavated the temperatures recorded in London during the summer of 1928 and assumed that instead of incubating his cultures before going on vacation, Fleming had just left them on his bench. The record shows that the August temperatures were in the 60s, favorable to the growth of only the molds, after which they rose to the 70s, suitable for the growth of the cocci; they grew everywhere except near the molds, which must have exuded a substance inhibiting their multiplication. But where did the mold come from? It turned out to be a very rare organism, unlikely to have flown in through the window, which in any case Fleming rarely opened.
Some years earlier a Dutch allergist had given lectures in London advancing the now accepted theory that some patients suffer from asthma because they are allergic to molds. As a result, the head of Fleming’s department at St. Mary’s, Sir Almroth Wright, appointed a young Irish mycologist, C.J. La Touche, to isolate molds from houses inhabited by asthma patients so that the molds could be identified and extracts made from them to desensitize the patients. Because molds produce myriads of airborne spores, mycologists normally grow them under hoods fitted with extract filters, but Wright favored the British string-and-sealing-wax tradition of research and made La Touche grow his molds in an open makeshift laboratory furnished only with tables. It so happened that this laboratory was immediately underneath Fleming’s. It was La Touche who identified Fleming’s mold as belonging to the Penicillium family. La Touche is not sure that it came from his collection, but both Hare and Macfarlane regard it as the most likely source. Hare concludes:
Such, then, is what I conceive to be the background to the discovery of penicillin. An accidental observation it is true, but what an accident, depending as it did on a whole series of apparently unrelated events. The choice of Fleming to write a chapter in a book; the publication of a paper in a scientific journal that prompted him to enquire further; lectures by a Dutch physician that led to the appointment of a mycologist; his working in a laboratory directly beneath that of Fleming; his having the good fortune to isolate a powerful penicillin-producing strain of the mould; his having inadequate apparatus so that the atmosphere became loaded with spores; the high probability that Fleming either forgot to incubate his culture plate or purposely omitted to do so; the fact that Fleming’s own laboratory was peculiarly sensitive to outside temperatures; that a cold spell came at a time of the year which is usually unsuitable for the discovery; the visit to Fleming by Pryce that led the former to look again at a plate he had already inspected and discarded; and its having escaped destruction because of entirely inadequate methods for the disposal of used culture plates. All these events, acting in concert, brought to Fleming’s notice a phenomenon that cannot, even now, be reproduced unless the conditions in which the experiment is carried out are exactly right. Had only one link in this chain been broken, Fleming would have missed his opportunity. And if, as Paul Ehrlich used to say, scientific discovery depends partly on Geld or money, partly on Geduld or patience, partly on Geschick or skill and partly on Glück or luck, it was the last of them that was almost entirely responsible for the discovery of penicillin. It was, surely, the supreme example in all scientific history, of the part that luck may play in the advancement of knowledge.3
Gwyn Macfarlane, Howard Florey: The Making of a Great Scientist (Oxford University Press, 1979).↩
Ronald Hare, The Birth of Penicillin (London: George Allen & Unwin Ltd., 1970).↩
Hare, The Birth of Penicillin.↩