Penicillin A Victory Over Death

A Victory Over Death

It was in France that the idea came to him, came during the noise and stench and dying of the trenches. The young Alexander Fleming, a trained and unusually promising bacteriologist, and therefore “reserved”, had surprised his friends and colleagues by volunteering for the trenches in 1914. He was shipped over, as a lieutenant in the R.A.M.C., and soon the wounded were coming into his hospital, hundred upon hundred of them, their wounds crawling with bacteria, and he realized, to his dismay, that there was little to aid them.
“Surrounded by all those infected wounds,” he wrote later, “by men who were suffering, dying, without our being able to do anything to help them, I was consumed by a desire to discover, after all this watching and waiting, something which would kill those microbes.”
And in his heart he knew that “something” would have to be a something which would help the body’s natural defences. The antiseptics then in use were worthless. Not only did they do nothing to prevent, for example, gangrene, they actually seemed to promote its development. For a surface wound, but there were few of these, they had some slight value: they destroyed the bacteria and, with them, because the wound was on the surface, only surface cells, which could be replaced. For deeper wounds, they were worse than useless, destroying irreplaceable tissue and at the same time seeming to destroy the body’s natural power to resist infection.
But the war ended in November, 1918, and two months later Alexander Fleming was demobilized, without having found an answer to the problem.
But he was thinking, he never stopped thinking, along the right lines. He knew that his substance would have to be something, perhaps from the body itself, which would encourage it to kill invaders itself, and three years later, in 1921, he took the first step forward. He had tried various human secretions and now he found that human tears, dropped into a culture of bacteria, dissolved them with startling speed. The substance in the tear-drop which had this effect he named “lysozyme” and he soon discovered that it was contained in nail-parings, hair and skin and even in certain leaves and stalks of plants.
Unfortunately, the lysozyme, so powerful against some bacteria, had practically no effect on the dangerous ones. Its immediate use was therefore limited; but it was, as we now realize, a tremendous step forward in bacteriology. Fleming read a paper on it to the august Medical Research Club in December of 1921 and was distressed when it got a chilly reception. Eight years later, he was to get exactly the same frigid reception for his first discovery of penicillin.
During those eight years, Fleming never stopped his research into that pet theory: that something from the human body, something living, was the answer to bacteria. Lysozyme, though it never became a practical proposition, seemed to prove him right.
Could lysozyme be improved, treated in some way to make it attack dangerous bacteria with the force it launched against harmless ones? Or would some other substance be the answer?
The answer came, quite suddenly, in Fleming’s London laboratory. The lab was bursting with bits of equipment, bunsen burners, crucibles, pipettes, test tubes, Petri dishes full of colonies of bacteria ripening for examination under the microscope, rubber tubes, glass jars. During the day, the cover had been taken off some of the Petri dishes to enable them to be studied under the microscope and now, as the Scots bacteriologist chatted to a young English visitor, he lifted the lids again, one by one and looked in. Several of the cultures, he noticed, had been contaminated by mould, but this was a common occurrence: the air was full of “spores” and when the tiny reproductive organs settled in a damp place they would proliferate, put out shoots in every direction, like a strawberry plant, become a fungus. It was tiresome, Fleming admitted, but that was all. “As soon as I uncover one of these dishes,” he said, “something just drops out of the air. Right into it.”
Suddenly he stopped talking. He bent over, looked carefully into one of the dishes.
On the surface of the culture of staphylococci which he had been breeding there was a growth of mould. It seemed exactly like the mould on practically all the other dishes, but on this one, round the edges of the fungus, the colonies of staphylococci had disappeared, vanished. If he looked carefully, he could see them, but, instead of being an opaque mass, they were simply drops of dew.
He picked up a small piece of the mould with his scalpel, put it in a test tube. To the younger doctor with him there was nothing at all surprising about the fungus and its effect on bacteria: the same thing would have happened, the bacteria would have been killed, if someone had dropped strong acid into the dish. Probably the fungus was exuding some acid. After all, it was easy enough to kill bacteria in a dish. The problem was to kill them in the human body, without killing the body in the process.
“This,” said Fleming, “is really quite interesting.” He scooped out the rest of the fungus, put it carefully into another test tube, corked it. Then he turned round, resumed the conversation.
“What struck me”, the young man was to write later, “was that he didn’t confine himself to observing, he took action at once. Lots of people observe a phenomenon, feeling it may be important, but they don’t get beyond being surprised.”
The next day, Fleming began to cultivate his mould. He took it from the two test tubes, spread it on a larger bowl of the nutritive broth which the laboratory used for breeding bacteria. The fungus grew, incredibly slowly, pushing out tentacles across the surface of the broth, becoming, centimetre by centimetre, a thick, soft, pockmarked mass of green and white and black. Fleming watched it for several days. Then, quite suddenly, the broth itself, having been a clear liquid, went a vivid yellow. Now he took a drop of this yellow liquid and placed it at the centre of the dish on which he had arranged, star-fashion, half a dozen different colonies of bacteria, each arm of the star being a different bacteria, streptococci, gono-cocci, staphylococci, and waited.
Breathless, he watched. Then slowly the colonies of bacteria, all of them, began to dissolve. Soon there was only the dew he had noticed before.
And now he knew, for these were serious, dangerous and even deadly bacteria, that he had found the answer to his problems. Lysozyme, his great hope of a few years back, had been almost useless against them. Ordinary antiseptics and disinfectants killed them, and killed the patient as well. This, and he was so sure of it he drank half a glassful, was a harmless substance. While he waited for any reaction he busied himself diluting the liquid and testing each dilution, from half-and-half to one part in five hundred. Still, though more slowly, it went on, killing bacteria.
It was important now to find out what the mould was, if he were ever to get any more of it, rather than having to rely on the slow breeding of the original spore which had landed on his bench. He knew almost nothing of mycology, the science of fungi, but he studied it, enlisted the help of experts, and soon was able to establish it as “penicillium notatum”, a penicillin, or fungus, of the “notatum” variety.
The problem, though, was to get more of it. A second problem, and more intractable, was getting the yellow liquid into a stable enough form to be stored and used when necessary: it lasted only a short time before degenerating into an inert, useless, liquid. These two problems held up the development of what Fleming knew was a wonder drug for over ten years. In the meantime, because he was unable to produce enough of it to demonstrate anything worth while, men scoffed at him.
From the day the spore blew in through Fleming’s Paddington window, he and others who believed in him never stopped working on the extraction and stabilization of the drug. Fleming was able to perform several minor but miraculous cures with the small quantities he was able to prepare, but there just was not sufficient to embark on a major test.
By the outbreak of war in 1939, ten years after the initial discovery, penicillin still could not be produced in adequate quantity or made stable. It had to be prepared from the mould—the pitifully small quantity of mould, for each treatment. Then, with government backing, a small team under the Australian Howard Florey got together in Oxford and determined to solve the problem. Gradually they found they were able to purify small quantities of the mould by a complicated method of evaporation, and the time came to try this new drug on a patient with something more seriously wrong with him than the boils and surface infections which Fleming had managed to cure.
News came that an Oxford policeman was dying of septicaemia from a small scratch at the corner of his mouth which had infected the blood stream. On 20 February, 1941, an intravenous injection of the purified penicillin was given to the dying man and thereafter every three hours. At the end of twenty-four hours the improvement was almost incredible.
Then, as Florey and his team had feared, the penicillin which they had laboured so long to produce ran out. The patient hung on for a few more days, but the microbes, no longer attacked by penicillin, seized the upper hand, and the man. died.
The drug just had to be made faster. To this end, Florey made inquiries in America, and at last the Northern Regional Research Laboratory of Peoria, Illinois, agreed to help. They had been working on uses for the organic by-products of agriculture and now, when they started work on the new drug from England, they discovered that corn-steep liquor, a by-product of maize, was an ideal medium for the growth of the penicillin fungus. They became enthusiastic, and within months Peoria was producing twenty times as much as Oxford. At the same time, they were on the look out for moulds which might give a larger yield of penicillin. Up to now every gramme of the drug that had been made had descended from the spore which landed on Fleming’s bench in 1929. Many experiments were made with moulds, but it was not until 1943 that the young woman the lab employed in Peoria to go round the markets cornering rotten fruit (they called her “Mouldy Mary”) brought back a melon. The mould from this, a “penicillium chrysogenum”, proved successful and remarkably productive.
Nowadays, almost all the penicillin in use is descended from one rotten melon bought in the market at Peoria, Illinois.
At last the real value of Fleming’s discovery was clear to everyone. Production, both in England and in America, mounted by leaps and bounds, and at first all of it was earmarked for the services. Thousands of dying soldiers, sailors and airmen were saved by the new Wonder Drug, and it was not until the end of 1944 that the military authorities felt themselves able to spare any of it for civilian patients. By this time the quiet, shy, sensitive man who had invented it had been honoured by his king and was now Sir Alexander Fleming. In the years before he died in 1955 he was showered with honours from every nation in the world.
Penicillin, the first of the “antibiotics”, substances produced by fungi or bacteria which inhibit the growth of other micro-organisms, was the biggest medical breakthrough in the first half of the twentieth century. It was and is startlingly effective against a wide range of diseases like pneumonia which had so often been fatal, and though it has no effect on the bacteria of, say, influenza and tuberculosis, other antibiotics, developed in the manner Fleming introduced, have been effective against these. The number of antibiotics, streptomycin, aureomycin, terrarnycin and numerous others, is increasing yearly. There is a danger that with too widespread a use of them, bacteria may become resistant; that some day the population may be exposed to an epidemic from a new and resistant strain of, say, tuberculosis. So far this danger has been kept at bay by the proliferation of new antibiotics which have ensured that most of the resistant strains of bacteria can be dealt with by another antibiotic to which they are not, yet, resistant.
The discovery of penicillin completely revolutionized the treatment of disease. The young doctor of today can hardly realize how helpless his predecessors felt against so many deadly infections. The average expectation of life has increased so greatly that the whole structure of society is altering. All this simply because a research worker believed in the possibility of a certain drug, and trained himself to recognize it the moment it appeared.