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The Life of Sir Alexander Fleming
Chapter XI - A new magic bullet: the sulphonamides

The chemist gives birth to the drug, but the doctor supports its first steps.


Thanks to Lord Beaverbrook, Lord Iveagh and others, St Mary's Hospital was growing. In 1931, The Duchess of York (later Queen of England, and now Queen Mother) laid the foundation-stone of the new Medical School. In 1933 the School and the Institute of Pathology and Research were opened by King George V. The buildings were huge. There was a lecture theatre and a real library, but many there were who mourned the happy days when they were pressed for space. It was then, they thought, that their best work had been done. The famous teas, now held in the great library, no longer had the same charm as had been theirs in the congested little room used by the Inoculation Department, where few books were seen upon the shelves. 'When a man wants to read books,' Wright used to grumble, 'he'd jolly well better write 'em.' It was only a 'crack', for who, if not he, had read the great books of the world?

Fleming very soon managed to recreate in his new home the familiar state of "ordered disorder'. String off parcels, elastic bands and empty cigarette boxes lay about everywhere. He hated to see his work-table neat and clean. All the things he needed — instruments, test-tubes and the rest — had to be exactly where he could lay his hands on them. 'The only chance I had of sweeping the place out and getting it a bit tidied up was when he was travelling or on holiday', says one of his old laboratory attendants. 'When he went away we did as much clearing up as we dared, and waited for the inevitable question as soon as he got back: "Who's been moving me?" One of his most frequent phrases was: "Just put that aside: it may come in useful." '

Games were now in high favour at St Mary's, as Wilson and Fleming had always hoped they would be. After 1930 the hospital had as many as five Rugby fifteens which greatly distinguished themselves, more than once winning the Inter-Hospitals Cup and since then giving four captains to the All-England side. No matter how bad the weather, Fleming never missed a cup final, and shouted 'Mary's!' as loudly as any student.

The renovated Medical School had a magnificent swimming-bath. In 1935, 1937 and 1938, St Mary's won the Inter-Hospitals Swimming Cup and, in 1938, the Water-Polo Cup. This delighted the veteran swimmer who was now Professor of Bacteriology. Needless to say, the tradition of excellence remained very much alive in the rifle club. Every year there was a match between students and teaching staff and, with shots like Fleming and Freeman, the staff ran a very good chance of winning.

One year the professors found a student posted at the entrance to the range, who in tones of authority was asking each competitor his age and noting it down.

'What's age got to do with it?'

'For each year over forty we give you a handicap of one point,' said the student, condescendingly.

This annoyed Fleming and, when his own turn came, he said, without moving a muscle of his face: 'Ninety.' The student gave a start, but, not daring to go back on what he had said, wrote down 'Handicap, 50.'

Though Fleming was now a man in middle life, Wright still treated him like a Victorian father. 'This young fellow Fleming is doing a lot of good work,' he once said patronizingly to a visitor. In 1928 Fleming had been appointed Professor of Bacteriology in the University of London. At the Institute, salaries were still arbitrary, and settled entirely by Wright. The principal resources of the Institute came from the manufacture and sale of vaccines. But vaccines and serums did not, alas! solve all problems where infections were concerned. Fleming had had sad proof of this in the death of his brother, John. They had been together at a match one day when an icy south-west wind was whipping the stands. Next morning John Fleming went down with pneumonia. Two years before he had been saved from a similar attack by anti-pneumococcal serum. This second onset of pneumonia belonged to the same type, but this time the serum had no effect. The magic bullet for use against the pneumococcus had not yet been found. It existed in the penicillium juice, but could not be purified. Consequently it was impossible to use it.

Since the brilliant victory of salvarsan over the pale spirochaete, research in chemotherapy had continued. Ehrlich had demonstrated an affinity between the doubly nitrogenous dyes and the bacteria, and their bactericidal power, in vitro. Chemists in the employment of the Bayer company of Germany succeeded in synthesizing a large number of such products, and entrusted them to one of their colleagues, Domagk, to try on previously infected mice. In 1932, Domagk discovered that a certain red dye protected most of the infected mice against the streptococci. How was this? Probably one part of the dye, uniting with the substance of the microbes, was destroying its chemical equilibrium and so causing their death. These results had been obtained with doses very much inferior to what constituted a danger to the cells of the body. This seemed to be an important discovery.

Domagk gave the name 'prontosil9 to this miraculous product. One of the first cases treated by him was that of his own daughter, who had become infected in the laboratory as the result of handling a culture of streptococci, and was saved by prontosil. For three years the tests continued in Germany without any publicity and almost in secret. Finally, in 1935, the discovery was solemnly announced to the scientific world. Domagk came to England and addressed the Royal Society of Medicine on the subject. Fleming was present on this occasion with Dr Young who was much impressed by the figures which Domagk had given. Fleming, on his way out, said to Holt: 'Yes, but penicillin can do better than that.3 The quantity used by Domagk seemed large to him, and the results less dramatic than those he had himself obtained. All the same, he had been much interested.

Wright, even after Domagk's visit, remained sceptical. Chemotherapy still inspired him with an invincible repugnance. It so often happened that substances about which marvellous things had been promised had later proved to be ineffective or dangerous. How was it possible, said Wright, that bacterial infections could be cured so quickly with a drug administered by mouth. The German statistics? Wright did not believe in statistics.

Fleming, however, with the lessons of lysozyme and penicillin behind him, was more receptive where novelties were concerned. He had no preconceived ideas on the subject and was prepared to accept the evidence of experiments, provided those experiments had been faultlessly carried out. To a friend, Dr Breen, he said: T rather think that this time we really are on to something. It's called "prontosil", and is put out by the Bayer people.' Breen, ever a sceptic, asked: 'D'you think you could get me a little?' T'll do my best,' Fleming replied and, a week later, gave a small quantity of prontosil to Breen, who tried it on several cases of erysipelas and, much to his surprise, cured them completely. Yes, it did seem as though, this time, the medical profession had 'got on to' something new.

In France, four research-workers — Trefouel, Madame Trefouel, Bovet and Nitti — at the Pasteur Institute in the department presided over by the great scientist, Ernest Fourneau, made under his direction a careful study of prontosil. Their curiosity was aroused by an odd fact: the drug which was so active in the body did not kill microbes in vitro. This seemed to indicate that the product, when introduced into the human body, underwent some sort of transformation and that an element, toxic for bacteria, was in some way released. The same sort of thing had happened with atoxyl which, as Ehrlich had shown, was changed in the body into a substance containing arsenic and, therefore, fatal to the trypanosomes.

Systematic study of certain derivatives closely allied to prontosil revealed the fact that the bacteriostatic activity was in each case connected with one part only of the molecule: the para-amino-phenyl-sulphonamide. The researchers of the Pasteur Institute, when they resumed their tests on this particularly simple molecule, found that, in fact, it alone was active. The hypothesis formulated by them was that prontosil when in the body became split, and this was later confirmed by the presence of para-amino-phenyl-sulphonamide in the blood and urine of patients who had been injected with prontosil.

This discovery completely altered the conditions of its use. Prontonsil had been patented by the Bayer company, which meant that sick people all over the world would be dependent on them for supplies, whereas sulphonamide, being a known substance, could be manufactured freely by any makers of chemical products. It had been long in use for the making of dyes because the extremely stable molecule gave an added fastness to those which contained it. It 'clung' to the streptococci as it 'clung' to the material to be dyed.

The medical people in England and in France adopted this new weapon against infection. 'The chemist', Professor Fourneau has written, 'gives birth to the drug, but the doctor supports its first steps.' The successes achieved in France, at the Pasteur Hospital, by Rene Martin and Albert Delaunay deeply impressed the world of medicine. In England the new product was 'launched', with a very complete study of its effects in cases of puerperal fever made by two specialists at Queen Charlotte's Hospital, Leonard Cole-brook and Meave Kenny (it will be remembered that Dr Colebrook had left St Mary's in 1930). Though Lister, many years before this, had considerably ameliorated the condition of lying-in by asepsis, the serious ailments attendant on child-bearing were still fairly frequent in the London hospitals, where the mortality rate stood at about 20 per cent. In 1936, Colebrook and Kenny were able to announce that this rate, in over sixty-four cases treated with prontosil, had diminished to 4.7 per cent. The control was furnished by the other London maternity cases in which the rate of 20 per cent had not varied. This demonstration appeared to be irrefutable.

Very soon sulphonamide (1162F) was recognized in all countries as effective, not only against streptococci, but also against meningococci, gonococci and perhaps certain kinds of filterable virus. The field of research was widened. The chemists sought to perfect this magic bullet, on one side by diminishing still further the toxicity of the sulphonamides (some people did not tolerate them well), and, on the other, by creating different compounds which might be able to attack still other microbes.

Fourneau and his school supplied some remarkable directives to the investigators by showing clearly the nature of the group of atoms responsible for the therapeutic activity, the group, that is, which 'clung' to the bacteria. The sulphonamides multiplied and then, as always happens, became the object of an excessive craze. The miraculous element pleased the masses, but, discounting that, the positive effects were considerable. The mortality rate in cases of cerebrospinal meningitis fell from 70 per cent to less than 10 per cent. In blennorrhagia complete cure was achieved in ten days for 90 per cent of cases. It could be said that antibacterial chemotherapy, as a successor to Ehrlich's antiparasitic chemotherapy, had at last been born. On the other hand, in regard to certain microbes, the sulphonamides appeared to be powerless, and the clinician was still left weaponless.

Furthermore, there had been cases in which bacteria installed in dead tissues or in pus appeared to be immune to attack. They produced protective substances which inhibited the effects of the sulphonamides. Fleming, a bacteriologist of the old school, who, so to speak, lived with his microbes and knew their habits, had announced, when the sulphonamides were still in their infancy, that resistant strains would develop if, for example, the gonococci were exposed to doses of a strength insufficient to kill them, and, indeed, it was not long before the undaunted gonococci outfaced the sulphonamides. 'This may be due to one of two causes', said Fleming. 'Either the more sensitive organisms have been eliminated by the drug, while the naturally less sensitive have survived, and, in reproducing themselves, have engendered whole resistant generations: or as a result of insufficient treatment, a microbe, once vulnerable, has acquired the power to resist.'

Reticent he might be, and silent too, but he could not help thinking that one day his child, penicillin, would do better than anything so far found. He was still hunting for a chemist who might solve the problem of purification. Douglas MacLeod, the gynaecologist , tells how once, in 1935, when he and Fleming were lunching together in the canteen at St Mary's, they exchanged views on the astonishing results obtained, thanks to prontosil, in cases of puerperal.fever. Fleming praised the new drug, but then, suddenly turning to his companion, said: 'You know, Mac, I've got something much better than prontosil, but no one'll listen to me> I can't get anyone to be interested in it, nor a chemist who will extract it for me.'

'I asked him what the substance was called. He said that he had given it the name "penicillin". I had to admit that I had never heard of it. He asked me to go with him to his laboratory, which I did. He showed me the mould, and actually gave me a specimen, which I still have. We discussed its possible use in gynaecology, and I suggested that it might be tried in certain cervical and vaginal infections. It was agreed between us that the experiment should be made of inserting the substance into the vagina, but the result was not satisfactory because the mould was quickly killed by the vaginal discharge.' MacLeod adds that Fleming asked him whether he knew any biochemist who might succeed, at long last, in extracting penicillin. T told him that I did know a very brilliant man, Dr Warren, but that he and I were trying just then, to find a way of determining sex during pregnancy. So nothing was done.'

Dr Breen tells how one Saturday at the Chelsea Arts Club he said to Fleming: T read somewhere that you've been talking about your discovery to a meeting of pharmacists ... that substance, you know ... what d'you call it?'

'I suppose you mean penicillin?'

'Yes,' said Breen. 'Does it really do all you say it can?'

Fleming immediately jumped down his throat: 'Of course. If it hadn't been true, I wouldn't have said it.'

Breen gave him a friendly tap on the shoulder: 'You know I didn't mean that. I just wanted you to tell me whether you think it will ever be possible to make practical use of the stuff. For instance, could I use it?'

Fleming stared into the distance for a moment and then said: 'I don't know. It's too unstable. It will have to be purified, and I can't do that by myself.'

The specialist in venereal diseases at St Mary's, Dr McElligott, though much younger than Fleming, was on very friendly terms with him. He often asked his advice not only on bacterial questions, but also on problems of diagnosis and administration of drugs. Fleming, after all, had been one of the first persons to use Ehrlich's 606 successfully in the treatment of syphilis at a time when the method was looked upon as revolutionary. He had followed the progress of some of his patients of those days and had seen with pride that the cure had been maintained.

Naturally he showed McElligott his famous culture which had been contaminated by the penicilhum. 'This could do a power of good to your patients.'

They had a long discussion on the possibility of getting penicilli n in contact with the gonococcus. But who would dare introduce a mould into the urethra at the risk of provoking a secondary fungus infection?

'From time to time', says McElligott, 'he would ask me to tea in the library of the Institute to meet Almroth Wright, and listen to that great oracle of Immunology. I remember describing the first results of treating gonorrhea with the sulphonamides, and Wright's incredulity at the successes we had had. In a way, he seemed annoyed that an antibacterial chemical agent should have proved to be so powerful.'

What was Fleming's attitude? He had his own well-proved methods for studying the effectiveness of an antibacterial drug and a firm belief in the importance of the natural powers of resistance in the body. He wanted to know to what extent leucocytes and sulphonamides could combine to destroy microbes. As opposed to the old-fashioned antiseptics which he had riddled with criticism during and after the war, the sulphonamides had no toxic effect upon the leucocytes, or only at concentrations very much in excess of those necessary for use against microbes. 'Such observations alone5, he wrote, 'would make it practically certain that these chemicals would be effective in the treatment of pyogenic infections, and, of course, this has been clinically established. In the study of new chemicals designed to combat bacterial infections in the body, investigations of this kind should never be omitted, and if this were done we should have fewer extravagant claims and more truth in the advertisements of antiseptic chemicals.'

In a series of papers read to the Royal Society of Medicine, he showed: (1) That the sulphonamides are specific in their action (that is to say that they exercise a powerful action on some bacteria but are without effect on others). (2) That where large numbers of the microbes are present, the sulphonamides have little or no antibacterial action. (3) That their action is essentially bacteriostatic and the natural defence mechanism of the body has to complete the destruction of the bacteria.

The experiments had been carried out with his very simple equipment: slide-cells, Petri dishes, grooves made in agar. By hollowing out two parallel ditches, the one filled with a sulphona-mide, the other with penicillin, and placing perpendicularly to them cultures, more or less diluted, of streptococci, he noticed that the penicillin proved active in all cases, whereas the sulphona-mide, though very effective against weak microbial dilutions, failed to inhibit the non-diluted cultures. Consequently, penicillin was more valuable, but the sulphonamides had in their favour the fact that they were stable and could exist in the pure state. For the moment, therefore, they carried the day.

And what about the vaccines? The St Mary's team continued to use them, not without success. In an article for the British Medical Journal, Fleming drew attention to several remarkable cures obtained with auto-vaccines. He was looking for a vaccine against influenza and other respiratory infections. As to the common cold, though admitting that, more often than not, it is caused by a virus-against which we have no weapon, he added that in many cases the cold is aggravated by a bacterial infection. Sometimes, even, the cold is purely bacterial and is due to the temporary aggravation of a chronic infectious condition. In this latter case the auto-vaccine could be of help.

Fleming advised a combination of vaccines and sulphonamides. He reasoned as follows: cThe effect of the sulphonamides, such as 693 M&B, is bacteriostatic. It facilitates the action of the leucocytes. But these are also reinforced by the presence of antibodies. Why not, by means of a vaccine, provoke the formation of these antibodies? The sulphonamides would be the more effective.' With his colleagues, Maclean and Rogers, he tried, by means of an experiment with infected mice, to compare the mortality rates of those which had been given 693 M&B without vaccine, vaccine without M&B, and, finally, vaccine and 693 M&B combined. The answer was clear. With a combination of the two substances, but only with that, all the mice were saved.

Experiments of this kind gave great pleasure to the Old Man. There was still room for immunotherapy. Relations between the Chief and Little Flem were excellent. Wright continued to pull Fleming's leg. Fleming took it all in good part and acted in precisely the way he knew was expected of him. In his turn, he pulled the legs of the young, who were fond of him because they knew that he was always ready to help them, and also because he was full of original ideas, no matter how extravagant those ideas might seem on the surface. Even in his gardening he advocated the most startling methods. Once, on his way to The Dhoon, he bought a great many bulbs of flowering plants, and suggested to an aviator friend that the best way of planting them would be by scattering from an aeroplane. In that way their dispersion would be governed by chance, said he, and therefore look more natural.

When he sketched unusual plans for his work in the lab, his colleagues used to say: 'What a card Flem is!' He never minded their fun, but sat, with a look of feigned solemnity, at his work-table, well aware that people always laugh at what is new. 'That'll be a success in the long run, you see if it isn't,' he would say. In most cases he was proved right.

Though he was, above all, an observer, he loved rational explanations, provided they were inspired, and confirmed, by the facts. He was entranced by a most 'attractive' theory put forward by Fildes to explain the action of chemical medicaments. This theory was that the chemotherapeutic products have a chemical structure so nearly analogous to that of one of the substances necessary for the maintenance of the cells in a state of health that the microbial organism confuses them one with the other. The microbe, therefore, absorbs the sulphonamides by mistake, and fills itself so full of them that it cannot, then, take on an additional load of the substances which it needs if it is to grow and multiply. This is what leads to its death, or makes it an easy prey for the natural defenders of the body. It was a brilliant piece of theorizing — if rather surprising.

In 1936 the Second International Congress of Microbiology was held. Fleming spoke of penicillin and demonstrated before an audience of his colleagues the experiment of the groove in the agar which the microbes had been unable to approach. Once again the degree of interest aroused was very small. He was to recall the occasion eleven years later, at the Fourth Congress. 'I spoke of penicillin in 1936,' he said, 'but I was lacking in eloquence, and nobody took any notice ... Here was something of extraordinary importance, which was published in 1929, and demonstrated at the Congress of 1936, but which was neglected by everyone for years ... It may be that in this Congress there is something like it. If there is, let us not miss it.*

Before his audience of 1936 he gave a number of other demonstrations, too, which, though less serious, amused him. Had any bacteriologist, previous to Fleming, had the idea of using the pigments of microbes for the purpose of painting? Probably not, but he certainly found this piece of professional relaxation great fun. Many microbes are brightly coloured: the staphylococcus is yellow, the bacillus prodigiosus red, the bacillus violaceus blue. With this living palette ready to his hand, he proceeded as follows. On a sheet of blotting-paper he drew his motif— a dancer, a mandarin, a Grenadier Guardsman or a flag. Then he laid the blotting-paper on the agar so that it might become nutritive, after which he coloured his design with broths of the appropriate cultures. All that remained was to put the blotting-paper into the incubator. As soon as the microbes developed, the picture showed up in colour. Sometimes, too, he constructed small rock gardens, on the soil of which penicillium laid a thick carpet of moss while the microbial colonies displayed a pattern of brilliantly coloured flowers.

One day, when Queen Mary paid an official visit to the hospital, he prepared a little exhibition of these bacterial fancies, dominated by a superb Union Jack, all in cultures. It appeared that the Queen was not amused, for she hurried past it. Perhaps she thought the game lacking in the seriousness appropriate to a learned institution, or maybe she considered that the microbes were unworthy of the Union Jack. But Fleming took a childlike pleasure in this strange art, and continued to produce gardens and ornamental borders which he mounted on cardboard, framed, and gave to his friends.

About this same time, he asked the Professor of Pharmacology (today, the Dean of the School of Pharmacy) to undertake the task of extracting penicillin. 'Unfortunately/ writes Professor Berry, 'and to my everlasting regret, I did not make an attempt to do so, nor did I see, as he did, its importance ... I remember the conversation very clearly. He seemed so completely convinced that his discovery had a great future. I recollect his prediction that, if only the substance could be purified, it would be possible to use it systematically in the human body.'

At a somewhat later date, in 1937, he spoke to Dr Laidlaw, a former worker in the laboratory, about penicillin. 'I have never forgotten the calm enthusiasm which he showed on that occasion.

"One day," he said, "someone will find a way of isolating the active principle, and of producing it on a large scale. Then we shall see it regularly used against the diseases caused by organisms which, I know, it can destroy." '

Such pieces of evidence could be multiplied indefinitely. We have only to think of Fleming's inflexible reserve to realize how firm his conviction must have been for him to have risked being snubbed so often, and that at a time when so many new experiments were demanding his attention. He returned again and again to the one he had carried out in 1928. There is something deeply moving in the spectacle of this shy man with his burning faith in the capital importance of a piece of research, trying, in vain, to persuade those who alone could have made its practical application possible, to see as he did. Not that they deserve blame. Every research-worker has his own problems which it is difficult for him to abandon in favour of the problems of others. Three times Fleming had seen a flicker of hope, and three times he had been disappointed.

As to his master, Almroth Wright, Fleming obviously could not turn to him for either money or staff. T have the feeling', writes Sir Henry Dale, 'that if Alexander Fleming had been working in an institute under a chief willing to accept, and even to find attractive, the possibility of antibacterial chemotherapy, things might have happened more quickly, and been taken farther. As Colebrook has made perfectly clear in his biography of Wright, the Old Man did not want to take an interest even in the sulphonamides. He just brushed them aside, and treated the discovery as though it had never been made.' All Wright's instincts were up in arms against penicillin. On the other hand, it is true that if Fleming had not been trained by Wright, he would not have devoted his whole life to waging war against the infections. Perhaps he would not have studied the antiseptics or the natural defences of the body, and perhaps he would not have discovered penicillin.

Even at the time of his worst disappointments, he never forgot what he owed to his old master. One day, when Dr J. Taylor said to him: Tt was easy for you to impose your ideas: you had a Wright to back you up,' Fleming replied, in a scarcely audible voice: 'No, on the contrary.' He said no more, and only smiled,

fondly and indulgently. His capacity for silence was matched only by his capacity for waiting — and hanging on.

He did hang on, and he did wait. Tirelessly, and with the utmost clarity, he described again and again what should be done in order to make quite certain of the value of a chemotherapeutic drug. 'The testing of a chemotherapeutic drug', he said, 'somewhat resembles the testing which we all had to undergo as students to see whether we were safe to let loose on the public as medical practitioners. I suggest it should consist of three examinations, two pre-clinical, the final, clinical.

'The first examination consists of an investigation into the power of the chemical to kill, or interfere with the growth of, a microbe in human blood. The easiest way to do this is by the slide-cell method.

'The second examination consists of injecting or otherwise introducing into the body of an animal the chemical, and then testing the blood of the animal at intervals afterwards to see if it has an enhanced anti-bacterial power.

'The third or final examination is the cure of infections in men and in laboratory animals by means of the drug, and examination of its toxicity to the organism as a whole ...'

Following the discovery of the sulphonamides, scientists the world over had been looking for a substance which would destroy certain microbes in the human body. At the Rockefeller Institute Dr Dubos was in charge of research work undertaken with the object of finding an antibiotic which would combat the pyogenic germs. His method, which was very ingenious, consisted in infecting soil with these bacteria in the hope that microorganisms, in acute competition with them, would develop by selection.

He made a culture from the infected soil and did, in fact, find there the bacillus brevis 3/4, which had an immensely powerful bactericidal effect on numerous and dangerous microbes. He was able to isolate the active substance, which he called 'tyrothricin', and established the fact that it was a mixture of two antibiotics: 'gramicid' and 'tyrocidin'. Unfortunately both were toxic for the kidneys, but they could effectively be used in local applications.

And so the torch was passed from continent to continent. The seekers were on the right road.

By 1939 Fleming, now Professor of Bacteriology and Deputy Director of the Institute, had made for himself an important place in his speciality. But he was close on fifty-eight and it seemed unlikely that he would establish any extraordinary discovery before reaching the retiring age. Of course there was that penicillin of his about which he never stopped talking, but even he seemed to have given up hope of ever seeing it purified.

After the serious alarm of September 1938 all clear-sighted men were convinced that war could not be far off. Early in 1939 Fleming, happening to run into one of his assistants, Peter Flood, stopped him and said with a smile: 'D'you know what'U happen to the lab. if war breaks out?'

The question came as a surprise to Flood: 'No,' he said.

'Well then, I'll tell you ... Most of the staff will be attached to the First Aid Service; the rest, you and I among them, will stay on here. There will be very few of us, and our job will be to carry on with the work of the lab. until the bombs drive us away.' Flood nodded. 'Don't worry,' went on Fleming, 'we'll find somewhere to work, and we shall all be in the same boat.'

Flood replied that that would suit him down to the ground, and Fleming's face lit up: 'That's what I thought you'd say.'

He had been quite prepared to accept the prospect of ending his career quietly and silently in the laboratory where he had spent all his life and then, at sixty-five, retiring to cultivate his garden at Barton Mills in an atmosphere of esteem and friendship, but not aureoled with glory. Nevertheless, there are some (Dr Dyson among them) who say that he seemed to be suffering from some secret sorrow, and that his brevity of speech and dry humour masked a melancholy occasioned by his almost complete inability to express himself or to confide in others. The general opinion was that he was happy in his own odd way. To Professor Pryce he once said that he couldn't understand people who took their lab. troubles home with them. No worry of that kind had ever kept him awake. The only thing he regretted was that he could never really 'loosen up'. But he accepted with resignation what nature, Scotland and research had made of him.

Dr Craddock, who knew him well, describes his personal form of happiness in the following words: 'He was something of a dilettante in his work, not at all the type of man who will go on, month in and month out, painfully slogging through hundreds of cultures, noting tiny differences, and then, after five years of extremely careful work, producing a classified table of variants in the same organism. He preferred something a bit more spectacular and exciting. He wanted to work at a task he enjoyed doing. Lysozyme had appealed to him enormously, and penicillin even more. It was an entirely new world, and he relished the flavour of it.

In his daily life what he delighted in were the odd and interesting things. I remember one occasion when he was driving with me in the country and noticed a hand-cart of an unusual type, which had been made by a village blacksmith for the purpose of wheeling heavy churns from a farm to the road where they were loaded on to a milk-lorry. He asked me to stop, and, there and then, made a sketch of the object which had aroused his curiosity by reason of the ingenuity of its construction.

'My son, aged ten, made a metal crane with his Meccano set, and Flem insisted on taking a photograph of it, because he thought it a skilful job.

'He was fascinated by the clay ovens which are still used in our old farm-houses. A faggot of wood is set to burn in them. When the clay is white-hot, the ash is raked out, and the meat pushed in to cook. The whole operation is performed by the stored heat of the walls. The simplicity of the method and the economy in fuel appealed to him.

'When I say that he was a dilettante, I don't mean to imply that he was like a butterfly flitting from one bright flower to another, but only that he was selective in the type of work he did. Having made his choice, he went straight to the heart of the problem more quickly than any man I have ever known. All his work was most carefully done. There was nothing superfluous in it. He was remarkably neat with his hands. It is said that once at St Mary's, when blood-transfusions were a novelty, a surgeon failed to find the vein in a child, and sent for somebody to fetch Fleming and he, without the slightest difficulty, made the transfusion into the external jugular vein.

'He liked to work in the laboratory for six or seven hours a day, regularly, but he was not one of those who willingly put in twelve

hours at a stretch. He had done it in his early years, at the time of the opsonic index, but now, fortunately, it was no longer necessary. He never idled, and got through more in six hours than others would in twelve. He adored his house and garden in the country and, in summer, would set off on Friday evenings with a light heart. But he was very glad, too, to start in again at the lab. on Monday morning, and go on with the work he loved.5 And so the years passed.

In August 1939 Fleming and his wife went to New York for the Third International Congress of Microbiology. There he met Dr Dubos whose work he much admired. Dubos asked him what had become of penicillin, which had seemed to be so full of promise. Fleming explained that he had given the product to one of the greatest chemists in London and had asked him to purify it; that the latter had said the body was too unstable, and that, from the chemical point of view, 'it looked as though it wasn't worth much.' In America, a certain Dr Roger Reid, who worked at the Pennsylvania College of Agriculture, had read Fleming's papers and decided to make them the subject of a thesis. He had asked the college authorities for a hundred dollars with which to carry out some experiments (infecting mice with pneumococci and then injecting them with juice from the mould and, also, injecting penicillin into cows suffering from mastitis). This modest request had been turned down and, when one of the professors had offered to finance the experiments out of his own pocket, he had been threatened with dismissal! Fleming also met at the Congress an American doctor, Alvin F. Coburn, who took a lively interest in lysozyme and in the microbes of the pharynx which put up a resistance to it.

It was a great source of happiness to Fleming to know that the researches made so carefully in his tiny lab. at St Mary's, had crossed the ocean and aroused the interest of far-distant scientists. The month of August was, as is so often the case in New York, damp and overpoweringly hot. There were threats of storm. But the most violent was the human storm now piling up in central Europe. On September 3rd war was declared. Fleming and his wife immediately took passage for England on board the Manhattan.

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