Florey Story

Howard Walter Florey was a great man and nomistake. He devoted the more important partof his professional life to a single wholly admirable purpose which he pursued until he achieved it, showing, in spite of many setbacks and rebuffs, the magnanimity that is the minimal entry qualification for being considered ‘great’. In a memorialaddress, Patrick Blackett likened Florey’s achievement to that of Jenner, Pasteur and Lister: but the public were so little aware of him that when Macfarlane first approached publishers with the notion of a biography, they wondered if he would not do better to write on Alexander Fleming instead. This, Macfarlane surmises, was because the public had already cast Fleming as the hero of the great penicillin story: he was a closer approximation than Howard Florey to the public’s stereotype of a great scientist, for, although a great scientist, Florey was the kind of man who would have been a success at anything he had chosen to turn his hand to. Macfarlane thinks the comparison of Florey with Jenner, Pasteur and Lister is specially aptbecause ‘the work of these three men forms a logical sequence with his own that spans, in the course of about 150 years, the gulf between almost totaltherapeutic helplessness and the virtual defeat of most of the important bacterialdiseases.’ Whatever the general public may have thought about him, Florey stood unsurpassably high in the estimation of his colleagues – that which meansmost to a scientist – and in due course they elected him head of their profession in England as President of the Royal Society.

It is fortunate for mankind that no Geneva convention prohibits the prosecution of germ warfare by germs themselves, among whom the struggle for existence is murderous and unremitting. Penicillin is one of a class of substances manufactured by moulds and bacteria – particularly soil bacteria, which live in deplorable conditions of squalor and overcrowding: these are substances which suppress the growth or multiplication of othermicroorganisms. Penicillin was discovered by Alexander Fleming: by luck, so it is believed, though in reality Fleming had been looking for something very like penicillin all his life. The only element of blind luck about the discovery of penicillin was that, unlike most antibiotics, penicillin is not poisonous to human beings and other higher animals: the reason is that penicillin interferes with metabolic processes peculiar to bacteria, whereas some other antibiotics like actinomycin and mitomycin are toxic because they obstruct a cellular activity common to bacteria and ourselves.

Before a good scientist tries to persuade others that he is on to something good, he must first convince himself. The first experiment that convinced Florey and his two colleagues, Norman Heatley and Ernst Chain, that they might be on to something occurred very shortly alter the German Army– ‘to the inexplicable surprise of the Allied Command – instead of dashing themselves to pieces on the Maginot line, drove their Panzer columns round the northern end of it, and swept between the British and French armies against almost no resistance until they reached the coast nearAbbeville’. At 11 a.m. on Saturday, 25 May, 1940, eight white mice received approximately eight times the minimal lethal number of streptococci. Four of these were set aside as controls, but four others received injections of penicillin – either a single injection of 10 milligrams or repeated injections of 5 milligrams.

The mice were watched all night (but of course). All four mice unprotected by penicillin haddied by 3.30 a.m. Heatley recordedthe details and cycled home in the black-out.Poor mice? Yes of course poor mice, but poor human beings too, don’t forget:

Next morning, Sunday 26th May, Florey came into the department to discover that the results of his experiment were clear-cut indeed. All four control mice were dead. Three of the treated mice were perfectly well; the fourth was not so well– though it survived for another two days. Chain arrived, and then Heatley, who had had very little sleep. They all recognised that this was a momentous occasion. What they said is not recorded, but memory has supplied subsequent writers with various versions. One might suppose that Heatley said very little, that Chain was excited, and that Florey’s reported comment ‘It looks quite promising’ would be entirely in character.

Animal experiments on a much larger scale soon made it clear that penicillin was indeed of great potential importance. The first published paper on the subject in the Lancet, by Chain, Florey, Gardner, Heatley, Jennings, Orr-Ewing and Sanders – the names are in alphabetical order – stated: ‘The results are clear-cut and show that penicillin is active in vivo against at least three of the organisms inhibited in vitro.’

Macfarlane’s account of the animal experiments and the first clinical trial is simple and straightforward, and all the more exciting for being so. It makes my heart pound still, although I know the outcome, for the thrill of reading about these great occasions does not diminish: scientists are like cricket-lovers who never tire of reading or recounting what Colin Milburn used to do to short balls on the leg side from Wesley Hall.

Florey’s and his colleagues’clear awareness of its importance raised the problem of what would become of theirstrain of Penicilliumif – as seemed entirely on the cards – theGerman Army were to reach Oxford and sackit: ‘The mould itself must be preserved, undetected. Florey, Heatley, and oneor two others smeared the spores of their strain of Penicilliumnotatum into the linings of their ordinary clothes where it would remain dormant but alive for years.’

Because of its potency and non-toxicity penicillin is the paradigm of antibacterial substances, but it is not without snags: the warfare between germs which, as I suggested above, leads to the formation of substances like penicillin leads also to the evolution of remarkably effective mechanisms of defence. One is the manufacture of the ferment penicillinase which destroys penicillin and thus protects bacteria from it. The widespread use of penicillin – sometimesinjudiciously often – has led to the evolution in many hospitals of strains of bacteria resistant to its action: once a mutant impervious to penicillin has arisen, natural selection soon brings it about that the mutant becomes the prevailing type in the population. It is not that penicillin has lost any virtue, but rather that bacteria have acquired a vice.

Another snag, exacerbated by the tendency of clinicians in the early days of penicillin to administer colossal intramuscular doses in the presence of substances known to immunologists as ‘adjuvants’, is that penicillin cangive rise to severe allergic reactions in a specially susceptible minority of those who receive it. The development of new antibiotics or new variants of penicillin has gone a long way to annul this disadvantage.

Among the difficulties associated with the production and use of penicillin, I have mentioned only the evolution of penicillin-resistant strains of bacteria, and the ability of penicillin to sensitise susceptible patients. The greatest snag of all was the sheer difficulty of producing quantities sufficient for clinical trials. But Florey’s School of Pathologybecame a pilot-scale production plant for the purpose, and it was natural that he should turn to the great pharmaceutical companies to make use of their great practical experience and know-how. One of the American companies, Merck, knew how only too well. According to Macfarlane’s account, NormanHeatley’s visit to share with them what he knew about the production of penicillin was marked by something much less than candour on the part of Merck, who had prepared applications for British and American patents covering the essential stages of production processes devised by the Oxford scientists and one of their own scientific officers:‘This fact was not generally appreciated until 1945, when British firms discovered that they had to pay royalties on their penicillinproduction.’ Whatever their moral shortcomings, the great pharmaceutical companies did in due course produce penicillin in adequateamounts – the consideration that mattered most. The complexity of the production of penicillin and the murkiness of its origin(‘see Macbeth, ActFour, Scene One,’ said Oxford wags not unwilling to poke fun at a discovery so obviously important) impeded the funding of Florey’s research, for in the Thirties Gerhard Domagk’s discoveries had ushered in the era of the sulphonamides, also powerful antibacterial agents. They, being synthetic organic chemicals, could be produced without cauldrons and the toil and trouble that go with them. It is clear that some know-alls serving on the Medical Research Council at the time must have resolved that the future of antibacterial therapy lay with these synthetic organic chemicals and not with‘biologicals’ such as penicillin, for, much to the annoyance of Florey and Chain, the MRC did not fund penicillin as handsomely as the occasion called for. Luckily, however, the Rockefeller Foundation helped out. The sums involved – of the order of hundreds of pounds – seem comically small by modern standards, but money went much further then.

A leading article in the Times on ‘Penicillium’ referred, without mentioning any names, to the research in progress in Oxford. Sir Almroth (‘stimulate the phagocytes!’) Wright addressed the Editor thus about his former pupil:

Sir,

   In the leading article on penicillin in your issue yesterday you refrained from putting the laurel wreath for this discovery round anyone’s brow. I would, with your permission, supplement your article by pointing out that, on the principle palmam qui meruit ferat, it should be decreed to Professor Alexander Fleming of this laboratory [St Mary’s Hospital]. For he is the discoverer of penicillin and was the author also of the original suggestion that this substance might prove to have important applications in medicine.

Ever since Wright’s letter, there have been attempts to make a cause out of the allocation of credit for the great discovery: first by comparing the contributions of Fleming and Florey, and more recently by comparing the contributions of Florey and Sir Ernst Chain. But no journalist will get any copy out of Macfarlane: he treats the whole subject wisely and temperately, as might be expected of a historian who is a distinguished scientist.

Human nature, unfortunately, is such that so great a discovery as that in which Fleming and Florey played crucially important parts is certain to be followed by jealous attempts to diminish it by finding evidence that it had all been thought of or done before. Certainly Pasteur recognised that germs engaged in germ warfare, and maybe the Chinese did put mouldy soya bean curds to therapeutic uses: but Alexander Fleming discovered penicillin, and Howard Florey was the prime mover in turning it into the most important therapeutic innovation of the 20th century. Both were necessary, but neither can be judged singly sufficient.

Relations between Florey’s team and Fleming were inevitably difficult. Florey did what was proper: that is to say, he acknowledged Fleming as the discoverer of penicillin in his first paper on the subject, but Fleming always felt he deserved more credit than he got, and referred often to ‘my brainchild’. ‘What have you been doing with my old penicillin?’ Fleming asked the Oxford team when he came down to visit Florey’s laboratory. Florey and Chain told him what they were doing and took him on a tour of the laboratory: ‘Fleming said almost nothing during this inspection and returned to London without comment or congratulation on what had been achieved.’ It is clear from Ronald Hare’s The Discovery of Penicillin (1970), upon which Macfarlane draws gratefully, that Fleming was an amateur in the big business of practical therapeutics, where Florey was every inch a pro.

Florey was the greatest experimental pathologist of his day. Penicillin was not his only – nor even his principal – interest: to judge by the quietly passionate persistence with which he studied the problem and persuaded all his young colleagues to do so too, the central interest of his scientific maturity was to elucidate what came to be called ‘the great lymphocyte mystery’. Lymphocytes are white blood corpuscles – those, as we now know, that transact immunological reactions. The lymphatic vessels of the body, which drain fluid from the tissues, unite into one major vessel, the thoracic duct, that empties its contents directly into the bloodstream. By this route thousands of millions of lymphocytes enter the bloodstream daily, but what becomes of them, and what is their function anyway? Whatever their intentions may have been, most of Florey’s young students and coworkers – among them a future Dean of the Harvard Medical School, a future head of the Medical Research Council and the future wife of the reviewer – found themselves trying to answer these questions. The problem was solved by Dr J.L. Gowans, the one who became head of the MRC: he found, contrary to orthodox opinion, that lymphocytes are relatively long-lived cells which circulate and re-circulate through the blood and lymph vessels. Like the chorus in a provincial production of Faust, lymphocytes in the bloodstream at any one moment disappear behind the scenes and re-enter by another route. Lymphocytes, moreover, are cells that manufacture antibodies and are responsible for the recognition, and ultimately the elimination, of foreign-tissue transplants and cells infected by viruses or transformed by the action of cancer-producing agents.

Another of Florey’s great interests was the nature and cause of atheromatosis, the formation in blood vessels of atheromata, the waxy plaques that sometimes threaten the free passage of blood in such important vessels as the coronary artery, which supplies blood to the great muscles of the heart.

As a man of action, determined to get results, Florey might easily have made some bitter enemies, but in reality he inspired a good deal of affection and admiration among colleagues, who to this day like exchanging Florey stories and laughing at their discomfiture when some characteristically sardonic or scathing remark of his cut them down to size. I wrote a long-winded paper on my work as a graduate student in his lab and showed it to Florey. When he handed it back to me, he said: ‘I don’t see what you’re getting at, Medawar. The paper doesn’t make sense to me.’ Later on, having learned better, I wrote a clear and simple paper for a journal Florey was particularly fond of and regularly read, and I was overjoyed when Florey passed me in one of the narrow lanes that wind through the science area in Oxford, twitted me in his usual style on having rushed precipitately into print, but added: ‘Your paper’s not at all bad, Medawar.’

Florey was extremely intelligent, clear-sighted and shrewd, but he was not an intellectual, and even at the height of his success he was a tiny bit scared of such people, for he was not always as sure of himself as might have been expected of a man so enormously successful. ‘Was that all right?’ Florey once said to me after giving an important lecture at the Royal Society, of which he was President. It was, but I thought it touching and endearing that he should still want to be assured of the good opinion of his juniors.

So deep was the impression made by Florey on his juniors that I do not believe any one of them could have written a life of Florey of which Florey would himself have disapproved. He would have liked Macfarlane’s life because it is simple and straightforward and sticks to the point without clever philosophical or psychological digressions. Florey might have made some amusedly self-depreciatory remark about the use of the word ‘great’, but if he had done so he would have been – as he seldom was – wrong.