What if Fleming had not discovered penicillin?

Abstract

What would have happened had Alexander Fleming not discovered penicillin in 1928? Perhaps the obvious answer is that, someone else would have discovered penicillin during 1930s and the Oxford group, would still have purified it sometime in the early 1940s. Here, however, in this counterfactual account of the penicillin story, it is argued that without Fleming, penicillin might still be undiscovered and the antibiotic age would never have dawned. As a result, many of the recent developments in medicine, such as organ transplantation, might have been delayed or, at best, made more hazardous. Penicillin might have come onto the scene a few years later but, had Fleming overlooked the discovery, it seems certain that penicillin would not have saved countless Allied lives, during and after D-Day. Instead of having enjoyed fifty and more years of the antibiotic age, it is argued here, that we would have had to rely upon highly developed sulphonamides, so-called “supasulfas”, and other chemically-derived antibacterial drugs. Indeed, it might be the case that, even well into this new millennium, the antibiotic age has yet to dawn, and medicine is still waiting for someone to chance upon penicillin. Here we discuss what might have happened had Fleming not discovered penicillin and come to the conclusion that the medical armoury available today would have been far different and might have relied solely upon highly developed varieties of sulphonamides or similar, synthetic, non-antibiotic antibacterial agents.

1. Introduction

It is September, 1928; a forty-seven year old man walks, somewhat wearily, up the steps to his place of work. He would rather not be there. Summer is not yet over and he has had to return to London because of an emergency, otherwise he would still be enjoying life at his rural cottage in Suffolk. On entering his room, one of his assistants exchanges pleasantries and he doubtless responds with a few mild curses. The man sits at the bench; he is a scientist and this is his laboratory. Casually, he picks up a few old petri dishes on which he has been growing bacteria. He glances through them until he comes to one that looks unusual. A colony of mould has somehow found its way into the dish and is dissolving the bacteria around it. He shows the unusual plate to his assistant who shows only mild interest and then hands it back without comment. The scientist has one last casual look, decides the phenomenon is of no importance, and drops the dish into a bucket of disinfectant. Our scientist then picks up his bag and hurries off to catch the train back to Suffolk, unaware that he has just thrown away the opportunity to save millions of lives, win a Nobel Prize and become one of the most famous and feted men in history.

The above is of course a counter-factual account of how Alexander Fleming failed to discover penicillin, the standard story having been given many times elsewhere (Diggins, 1999; Garrod, 1947; Hare, 1982; Lignam, 2000; Wainwright and Swan, 1986; Wainwright, 1987, 1990, 2008).

Andrew Roberts, in the introduction to What Might Have Been, a book devoted to counterfactual studies, suggests that while battles, and many other events in history, can be successfully studied from a counterfactual perspective, the exposure of scientific discoveries to such a process tends to be less successful (Roberts, 2004). This is simply because, it is generally assumed, that if a scientist misses a discovery then sooner or later someone else will get there; gravity for example, would have still be open to discovery had Sir Isaac Newton never seen an apple tree!. However, here I wish to suggest that had Fleming not discovered penicillin then it is likely that, the first and most important of the antibiotics would remain undiscovered. There would also have been various time-related consequences; notably, insufficient penicillin would have been available for use by the Allies from D-Day onwards and other antibiotics (notably, the anti-TB drug, streptomycin) might never have been developed in time to back a number of major developments in modern surgery such as open heart and transplant surgery.

But, if Fleming had missed his chance, surely someone else would have discovered penicillin? Possibly, but it should be remembered that penicillin, although discovered by Fleming in 1928, was not purified and developed for medicine until the early 1940s, and there is no reason to believe that anyone was close to discovering penicillin in the interim. At best, without Fleming’s discovery penicillin would have languished for perhaps another five or ten years.

Let us begin our counterfactual journey by going back to that fateful moment in September, 1928 when Fleming missed the opportunity to discover penicillin…what happened next?

Has as we have seen, although Fleming discovered penicillin in 1928 and wrote his first penicillin paper in 1929, the drug was not made available for medical use (and then largely restricted to the military) until the early nineteen forties, following the intervention of Florey, Chain and co-workers at the Oxford University. Of course penicillin could have been discovered the day after Fleming missed the opportunity, but in reality there was no parallel discovery took place. As a result, anyone taking an interest in penicillin during the 1930s did so in the knowledge of Fleming’s work. In particular, there seems no reason to believe that Florey and Chain would have discovered penicillin, since their work depended on Fleming’s famous paper and their access to one of his penicillin-producing cultures.

Since penicillin was, in reality, not available during the 1930s few events and lives would have been materially altered if Fleming had missed the discovery. Fleming’s first penicillin paper refers to its use as an additives to bacteriological media to selectively isolate the bacterium Bacillus influenzae, then thought to cause influenza. A couple of workers reported using penicillin in this way, but their work was far from earth shattering, and the world of medicine would have happily continued without it. Similarly, without Fleming’s discovery an American student, called Roger Reid, would have needed to find another research topic for his MS thesis; no doubt his supervisor would have come up with another topic and the young man’s career would not have suffered unduly.

The absence of penicillin in the 1930s would however, have had more serious consequences for the lives of three people living in the steel city of Sheffield in England, who benefited from treatment with penicillin-rich filtrates. In 1930 such filtrates were used by Cecil George Paine to cure infections which might have left the children blind. Paine had worked in Fleming’s laboratory (and had seen the famous plate). On graduating, he left London to work in Sheffield. This, his first job, was described as being conjoint, that is his efforts were to be divided acting as a Pathologist at the Royal Infirmary and lecturing at the nearby Sheffield University. The young man, was required to do some research and remembering the penicillin plate, he obtained a culture of the penicillin-producing mould from Fleming. This, he cultured and used penicillin-rich filtrates to treat infections. His first attempts, against the skin infection sychosis barbae were unsuccessful, so he turned his attention to eye infections, arguing that the penicillin filtrates would be more likely to reach pathogens in the eye, than in puss-rich skin infections. Paine treated three eye patients, a local coal miner, whose eye had become infected after an accident, and two new born babies. All the infections were cured by the simple act of irrigating the infected eye with mould filtrates. The two babies were suffering from ophthalmia neonatorum caused by Gonococcus and diphtheroids. Such infections in the new-born were common before the advent of purified penicillin and nearly half of those who suffered from such infections were permanently blinded; by using penicillin, Paine therefore, potentially, saved the eyesight of all three of his patients. Unfortunately, Paine never published his work and penicillin continued to languish until 1939, when the Oxford workers began to take an interest in it.

Contrary to what is often said, Fleming did not lose interest in penicillin in the 1930s but continued working on it until almost the point when the Oxford Group began their work, but except for Paine’s, unpublished work, the existence of penicillin at this time had no impact whatsoever on medicine.

What then might have happened next? Would penicillin have remained undiscovered, or would someone else have chanced upon it, perhaps by a less serendipitous route that fate offered Fleming.

The first obvious question is – would the Oxford Group have discovered penicillin without Fleming’s intervention? The answer is – most probably not. The Oxford workers became interested in penicillin when Ernst Chain began to search the literature on naturally occurring antibacterial agents. After an extensive literature search, Chain concentrated on three potentially useful substances, an agent produced by B. subtilis, another bacterial agent called pyocyanase and (after reading Fleming’s paper) penicillin. He began with an abortive study of pyocyanase but soon turned his attention to penicillin. Amazingly, a culture of Fleming’s mould was already kept at Oxford enabling Chain to make an immediate start on the purification of penicillin. The rest is history penicillin was purified and, with American help, eventually produced in vast quantities, sufficient to help the Allies win the War. Without Fleming’s discovery Chain would have never chanced upon his paper and began his work on penicillin.

Florey was aware of penicillin from its inception. He had been on editorial board of the British Journal of Experimental Pathology which accepted Fleming’s paper and, because of his background, probably reviewed the paper. Paine also informed him about his therapeutic success with crude penicillin while he was the Professor at Sheffield University. Even with this background however, Florey seems never to have insisted that Chain initially concentrated on penicillin.

Was anyone else close to discovering penicillin as the decade of 1940s began? The simple answer is No. An American scientist named Bornstein provided a non-clinical paper on penicillin in 1940 and it has also been suggested that an American pharmaceutical company took an interest around the same time. However, both of these were developments based on Fleming’s discovery.

During the late 1930s however, a potentially important breakthrough in the development of antibacterial agents did occur with the discovery, by Rene Dubois, of gramicidin (Hotchkiss, 1990). Dubois found that a soil bacterium could produce bactericidal extracts from which was obtained the antibiotics gramicidin and tyrothricin. Unfortunately both compounds were found to be toxic and cannot be given intravenously; not surprisingly, their medical use is limited as topical antibacterial agents.

One might imagine that the discovery of gramicidin, despite its limitations, would have induced individuals and pharmaceutical companies to begin systematic searches for antibiotic–producing microorganisms that would inevitably have led to penicillin. Surprisingly however, such searches never materialised until after penicillin was introduced into medicine (Bennett and Chung, 2001).

Might other antibiotics have been discovered had penicillin not been discovered in 1928? To answer this question we have to consider the work of the Rutgers soil microbiologist, Selman Waksman. Waksman’s work was pivotal in the development of the post-penicillin antibiotics. As early as 1937, he reported studies on antagonism between soil microorganisms, and in 1940 he published a paper on the soil as a source of microbes capable of antagonising the growth of human pathogenic bacteria. Surprisingly however, none of this work relates to the production of antibiotics (a term indecently coined by Waksman), but instead it was concerned with the factors influencing the survival of a pathogenic bacteria in soils. Eventually however, Waksman and his co-workers did begin a systematic search for antibiotic which gave us a number of antibiotics, most notably the anti-TB compound, streptomycin. Waksman was heralded as the “the father of the antibiotics”, but what induced him to begin a searching for antibiotics? The answer is penicillin; without which, Waksman would never have begun his search for novel antibiotics. We know this to be true, because Waksman said that his decision to search for antibiotics (notably from a group of bacteria called actinomycetes) resulted from seeing what “these English scientists are doing with penicillin.” So, no Fleming, no penicillin – no work on penicillin by the Oxford Group and no antibiotics (including streptomycin) from Waksman’s laboratory.

The most important consequence of this counter historical chain of events then would have been the absence of streptomycin, an antibiotic which, when used with PAS, was the first effective treatment for tuberculosis. Without streptomycin, TB would have continued to have been a major scourge throughout 1940s and 1950s.

One person whose life would have been altered in a major way, had streptomycin never appeared would have been its co-discovery, and one of Waksman’s PhD students, Albert Schatz. Schatz was the senior author on the first streptomycin paper, and despite being legally defined as co-discoverer, did not share in the Nobel Prize for streptomycin which was given to Waksman alone. In order to win credit for his role in the discovery of streptomycin and a share in the royalties, Schatz had to take legal action against the Waksman and Rutgers University. Although successful, the US academic establishment began to see him a troublemaker and he was effectively ostracised from American academia. Without streptomycin Schatz would doubtless have been poorer and less notorious, but would have probably obtained a PhD in some other aspect of microbiology. Doubtless he would have gone on to a productive academic life, devoting himself to his first love, soil microbiology.

So without Fleming penicillin, and the other antibiotics now in a wide use, might never have been discovered. Would we then be totally at the mercy of disease? Fortunately not, because there came into use a class of drugs that would have provided an, albeit imperfect, alternative to the antibiotics. These compounds were the sulphonamides, or sulpha drugs, which although antibacterial, are not strictly antibiotics, (by definition an antibiotic must be made by microorganisms, or at the very least by living things).

The sulphonamides are however, relatively effective antibacterial agents and continue to be used in modern medicine (Kucers and Bennett, 1975). The first sulphonamides entered medicine during the mid 1930s and immediately had a major impact on the treatment of bacterial infections, most notably septicemia and childbed fever. Alexander Fleming spent considerable time during the mid-1930s researching this compound. When they first came into use they appeared miraculous, but of course they were soon eclipsed by penicillin and subsequent antibiotics. Had the golden age of antibiotics never happened then the sulphonamides would inevitably have been used more widely. No doubt more effective derivatives would have been found (what we might call “supasulfurs”); these compounds might equalled or even bettered the antibiotics. It is noteworthy that a major compendium of the use of antibiotics says this about the clinical use of the sulphonamides:

“There are now very few specific indications for sulfonamides, because of the wide range of available antibiotics”.

Clearly the situation might have been different if there were no antibiotics to fall back on. The development of “supasulphas” might even have prevented the development of the antibiotics during the say in 1960s, since the pharmaceutical industry might have argued that the sulphonamides were doing the job and there was little need to invest large amounts of capital and expertise was needed to extract antibacterial agents from messy mould juices. It is interesting to look back and see in what regard the sulphonamides were held, even as 1947, when the medial bacteriologist L.P. Garrod made some counter historical comments of his own. In reviews of Master’s book, Garrod pondered on what might have happened had penicillin been purified in 1930 and commented it would have meant that the sulphonamides would probably never have appeared, a possibility that he suggested would have “rendered the world as a whole poorer.” However, had a commitment been made around this time to antibiotic discovery and production developments in biotechnology would have been such that these compounds would have been rapidly developed from discovery, through purification to large-scale production. Conversely the pharmaceutical industry would not have been able to rely upon the vast amount of Government funding and critical sense of wartime urgency that gave us penicillin in 1940s.

The axis powers fought the Second World War without penicillin, instead relying upon the sulpha drugs. Despite the fact that the Germans and their Allies were at a considerable disadvantage, the sulphonamides did a relatively good job at reducing battle casualties. There is no doubt however, that, without penicillin, Allied casualties from D-Day onwards would have been far greater than they were. This brings us to, yet another, interesting scenario. There is evidence to suggest that Hitler’s doctor used penicillin to treat the Fuhrer after the Staffenberg assassination attempt of 20th July, 1944 (Wainwright, 2004). Without this treatment, Hitler might have died and the Germans might then have sued for peace a likelihood that takes us into a yet more complex realm of counterfactual speculation. Interestingly, the sulphonamides saved Churchill’s life when he suffered from pneumonia in Cairo in 1943. What would have happened in a world that, from 1942 onwards, in which the pivotal figure of Winston Churchill was absent?

What effect would Fleming’s failure to discover penicillin have had on the lives of the major figures involved in antibiotics era? Undoubtedly, all of the major players would (had they not made an unconnected, major discovery) have been forgotten and none of them would have received knighthoods, Nobel Prizes, or the other accolades that were showered upon them. Instead these accolades might have fallen to Gerard Domagk and the unknown pioneers who might later have developed the “supasulfas”. Doubtless Domagk would have been the subject of numerous biographies and TV documentaries, and children’s books, would simply relate the story of how the Nazis prevented him from accepting the Nobel Prize for Physiology and Medicine.

It is often automatically assumed that had Fleming not discovered penicillin then someone else would have. This could obviously have happened, but probably not in time to enable penicillin to save so many Allied lives from D-Day onwards. While the view that the sulphonamides would have successfully replaced the antibiotics is debatable, it is certain that we would be facing the same problems with sulphonamide, resistance as we are with antibiotic resistance.

Alexander Fleming is often criticised for not being more pro-active in developing penicillin as a curative agent. Interestingly, it has recently come to light that a research grant was made to the UK Medical Research Council, as early as 1930 for Stuart Craddock, one of Fleming’s assistants who, during this period, worked on penicillin. The request was refused, and the page detailing the proposed grant has mysteriously been excised from, the otherwise complete, MRC records. Maybe someone was keen to avoid the ridicule for having refused to support the work that would possibly have made penicillin available a decade sooner. Perhaps the perpetrator of this academic crime should have relaxed, since it is unlikely that penicillin could have been produced, on an industrial scale, during the early 1930s and had it been so, then the axis powers could have shared its benefits during the Second World War.

In conclusion, why not take this fantasy even further? It is June of 2013, a microbiologist with a lifetime’s experience of growing fungi and bacteria enters his university and picks up a contaminated petri dish.

“That’s funny!” he says.

This is how “Professor X” came to discover penicillin towards the end of the first decade of the new millennium. Unfortunately, his discovery will probably come to nothing. Why would anyone be interested in the expensive development of this new antibacterial agent? Might the consensus be -We have the supersulfas, what could possibly beat them? Why should anyone waste time and money trying to purify some messy mould juice? Stick to the supersulfas, that is where the future of medicine lies.