The Faber Book of Science

by John Carey

  It is a case of ‘the world is too much with us’; too banal to wonder at. Those other things we paused over, the building and shaping of the eye-ball, and the establishing of its nerve connections with the right points of the brain, all those other things and the rest pertaining to them we called in chemistry and physics and final causes to explain to us. And they did so, with promise of more help to come.

  But this last, not the eye, but the ‘seeing’ by the brain behind the eye? Physics and chemistry there are silent to our every question. All they say to us is that the brain is theirs, that without the brain which is theirs the seeing is not. But as to how? They vouchsafe us not a word.

  Source: Sir Charles Sherrington, Man on His Nature, 2nd edition, Cambridge, Cambridge University Press, 1951.

  *E. G. Drury, ‘Psyche and the Physiologists’ and other Essays on Sensation (London, 1938), p. 4.

  Green Mould in the Wind

  Alexander Fleming (1881–1955), a Scottish farmer’s son, began his working life as a clerk in a London shipping company. But in 1902 he won a scholarship to medical school and, after graduating, became a research bacteriologist. Service in France with the Medical Corps in the First World War developed his interest in preventing infection in wounds. After the war, at St Mary’s Hospital, London, he discovered an enzyme, contained in tears and other bodily fluids, and in egg white, that dissolved bacteria. He called it lysozyme (meaning ‘dissolving enzyme’). As it dissolved only relatively harmless bacteria, however, it was of no practical use. His next discovery was far more momentous. It is described here by Sarah Riedman and Elton Gustafson in their book on Nobel Prize-winners in Medicine.

  In a laboratory at St Mary’s Hospital in London there sat a row of petri dishes – those little plates on which bacteriologists grow microbes on a layer of solidified gelatin or agar. It was the workshop of Dr Alexander Fleming, a modest little man with shaggy brows and wire-rimmed spectacles. In the back of his mind he had long held the idea that he would like to find a better way to treat wounds than with harsh antiseptics. Even if they killed some bacteria, these chemicals did greater damage to the white blood cells. One morning in September 1928, he was doing some routine experiments, examining milky-white cultures. They contained colonies of staphylococcus (spherical organisms growing in groups of four), the germ that causes ugly boils. His eye fell on one petri dish that had become contaminated with a green mould.

  Contamination is the curse of bacteriological work. Researchers are as familiar with these microbic ‘weeds’ as the farmer is with unwanted invaders among his planted crops. Bacteriologists just throw the cultures down the drain, and are glad when not too much work has gone into nurturing the particular spoiled crop of colonies. In Fleming’s dish, a casual wanderer had drifted in through the window in a blast of dusty London air, and had settled itself among the staph colonies he was studying.

  Fleming was just about to discard the contaminated contents, but before doing so he took another look. This was different, and he made a note of it: ‘It was astonishing that for some considerable distance around the mould growth the staphylococcal colonies were undergoing lysis. What had formerly been a well-grown colony was now a faint shadow of its former self.’ It suddenly struck him about this lysis’ – something was dissolving his microbes! ‘I was sufficiently interested to pursue the subject,’ he later reported.

  With a loop at the end of a platinum wire, the most used tool of microbe searchers, he fished up a speck of the mould from the colony and placed it in peptone broth, the food moulds feed on. As it grew there, he saw first a fuzzy white, then a tufted green mass. When he examined it under his microscope he decided that the ‘weed’ belonged to a large family of moulds – Penicillium (from the Latin, meaning little brush) – which streak roquefort cheese green and spoil apples and oranges. Someone else might have given it no more thought, but in Fleming’s brain the wheels were set in motion – especially those that had been turning around the idea of benign antiseptics.

  He called to his helpers, for his vague hunch would have to be worked on. If this mould was brewing a juice that killed his bug colonies, he would have to look for it in the broth in which it was flourishing. So he filtered off some of the mould filtrate and dropped a bit of it on the glass plate in which his healthy staph colonies were growing. Sure enough, after several hours his bacteria died, disappearing under his very eyes as he examined a speck of the culture through his lens.

  Together with his assistants he began to dilute the mould-containing broth, finding that in one-hundredth of its strength it decimated the bacteria. Further and further dilutions still retained their killing power, several times as potent as pure carbolic acid, which, while killing bacteria, also burns the tissues. They repeated the procedure with other organisms, the deadly germs pneumococci and streptococci. These, too, were killed as surely as his staphs. But what would it do to animal tissues?

  To find out, they next brought in the usual inhabitants of bacteriology laboratories: mice, rabbits – the living test-tubes. Into the bellies of the mice, and into the blood vessels that stand out plainly through the transparent tissues of rabbits’ ears, he slipped his hypodermic needle, injecting a thimbleful of the broth from the syringe. If this mould filtrate was poisonous, his animals would soon show its effects. But the mice and rabbits showed no more effect than if he had given them salt water.

  This was indeed a find worth recording: ‘It has been demonstrated that a species of Penicillium produces in culture a very powerful antibacterial substance,’ Fleming put down in his notes. ‘It is a more powerful inhibitory agent than carbolic acid and it can be applied to an infected surface undiluted as it is non-irritating and non-toxic’ He christened his remarkable substance penicillin.

  Not being a chemist, he did not try to separate the microbe killer from the broth. But he did go on to other experiments, finding that the substance did not slay other bacteria – those that caused typhoid fever, dysentery and other infections in intestinal disease. On a fresh plate of jelly-like agar he dropped some of his own saliva, which contains the myriad different bacteria in the mouth. When, in the warmth of the incubator, the assorted colonies grew in profusion, he added penicillin. Some colonies were wiped out; others continued to thrive. Ergo! Those that were destroyed were sensitive to penicillin; the others were helpless against this mould antiseptic. In this way, one could detect the bacillus in influenza when sputum smeared on an agar plate was treated with penicillin. The influenza bacillus wasn’t touched by penicillin, and here was a convenient way to detect it in sputum!

  When he published his results in 1929, he suggested that penicillin could be used as a helpful laboratory tool to separate the ‘goats from the sheep’, as it were, in a mixed culture.

  This accidental discovery in Fleming’s laboratory was close to being miraculous. How easily it could have been missed without the world ever being the wiser! Luckily it happened to a man to whom Pasteur would have applied his now famous saying: ‘Chance only favours the mind prepared for it.’ Fleming himself once said: ‘Do not wait for fortune to smile on you; prepare yourself with knowledge.’

  Fleming maintained the culture, and sent it on request to laboratories around the world. However, he and his co-workers were unable to extract pure penicillin from the penicillium broth. This task was taken up in 1935 by the Australian doctor Howard Florey (1898–1968), working in Oxford with the chemist Dr Ernst Boris Chain, a refugee from Hitler’s terror.

  The division of labour was between the microbe growers, whose job it was to find the right food, temperature, and habitat for the mould, and the chemist, who was to try to coax the pure substance out of the broth. His chore was particularly difficult because the fragile active substance presented many knotty problems in separation and purification.

  During several months of trial with various solvents, Chain came closer and closer to the one that would pull out the killing substance from the filtrate. Then it was necessary to separate it from
the solvent. What was left was a little bit of brown powder. The bacteriologists took up once more from here. They dropped tiny flecks of the powder onto the culture plates to test their action on the bacteria. To gain some idea of its power is to realize that one part in two million dilution checked the growth of the colonies of the disease-producing bacteria.

  But was the killer safe to use in animals? Florey, the doctor, directed the next step – to see what penicillin would do inside the tissues of mice, rats, and rabbits. It passed this test too: the animals were none the worse for having shots of penicillin. One more question had to be answered: what would it do in animals infected with lethal bacteria?

  Florey called for dozens of mice to which he gave killing doses of staphylococcus – an organism that causes clean wounds to become infected. These test animals he divided into two groups: one received injections of penicillin every three hours, the other group did not. Then he watched his mute ‘patients’. Later, those that had not received penicillin began to sicken and die and within twenty-four hours they were all dead. During the same period those that were getting the medicine also sickened; they were bedraggled, miserable little mice almost overwhelmed by the deadly germs multiplying in their blood. But then came a turning point: they began to get better, some faster than others, until by the end of a week of regular injections of penicillin, all but one were alive and frisky.

  Penicillin had passed the animal test too. It killed streptococci and staphylococci without harm to the animals’ tissues. The team was convinced that penicillin was a good performer and would be safe to try in a human being. But now they were thwarted by a mechanical problem – how to get enough of the germ-killer to treat a man who required several thousand times the dose that would do for an infected mouse. Not only was penicillin hard to obtain in any quantity, it did not remain long enough in the blood. The material had to be injected every few hours to replace the amount that spilled over into the urine of the animals. ‘You might just as well try to fill a bathtub when the plug is out,’ Florey remarked.

  It was chiefly a problem of making enough of the active material. The work of brewing broth filtrate and separating the brown medicine was intensified. Finally, working day and night, the laboratory workers extracted enough material from the many batches to supply a human. About a teaspoon of the powder was turned over to Dr Mary Florey, the chief researcher’s wife, to try on a desperately sick patient.

  A policeman was lying gravely ill in Radcliffe Hospital at Oxford University. He had nicked himself while shaving and the tiny wound had become infected with staphylococci which had entered the blood. His face was covered with discharging abscesses and he was burning with a fever of 105 degrees. The abscesses were teeming with pus-forming staph and strep. The sulfa drug he had been given was helpless against this rapidly spreading infection. Dr Florey went to work on 12 February 1941.

  The brown powder was dissolved in salt water, and from a glass bottle suspended high above the bed the drug dripped down a rubber tube and through a large hypodermic needle inserted into the vein of the patient’s arm. For three days it trickled into the policeman’s blood, as the doctors watched the fever go down and the abscesses slowly getting better. Not to waste the limited supply, the patient’s urine was collected so that Dr Chain could reclaim the material discarded by the kidneys. But after the fifth day, just as the patient was definitely getting better, the penicillin gave out and couldn’t be replaced rapidly enough. As a result it was not possible to save the patient. More of the drug was acquired by careful hoarding and tried on a second patient who also died because again the small supply became exhausted. Despite these tragedies, due to scarcity of the drug, penicillin was definitely established as a microbe-killer. Then a third patient, a fifteen-year-old boy with an infected wound from an operation, was saved with penicillin recovered from the urine of the first two. The fourth, fifth and sixth patients also were cured.

  Clearly, the problem now was one of taking the production of penicillin out of the laboratory, and going into large-scale manufacture. It was 1941, the darkest time of the war in Europe. In England, fighting for its very existence, mass production was out of the question. Yet the need for this miracle drug was most acute – more soldiers were dying on the battlefields from infected wounds than from direct hits. There was only one place to which the London research team could turn for help – the United States.

  Florey and one of his bacteriologist-assistants were brought to America by a grant from the Rockefeller Foundation. The purpose of the mission was to find a way to increase the yield of penicillin from the mould and to manufacture it on a commercial scale. In this project the researchers secured the support of both the U.S. Department of Agriculture and several American drug companies. This was a giant cooperative effort involving research team, government, and industry. Starting with a tube of mould from Fleming’s original culture, brought over by Florey, penicillin was made to grow in gargantuan fermentation tanks, each with a capacity of 12,000 gallons.

  The story of how high-yielding mould strains were found, and the methods for purifying penicillin developed (absolutely pure penicillin is white instead of brown) requires a book in itself. The mould culture was taken from small flasks and milk bottles to huge fermentation vats; the fodder used – corn-steep and milk sugar – brought a greater harvest; sterile air under pressure and ultra-violet light prevented contamination. By the end of 1943 production was five billion units a month, and at the end of the following year, 300 billion units – enough to treat a half million human beings each month.

  Thus, human ingenuity, efficiency, and industry solved the problem of the limited supply of penicillin, and no one had to die for lack of the drug. Penicillin could now be tested – and successfully – in patients not only with infected wounds, but with crippling heart disease, syphilis, gonorrhoea, discharging ears, certain types of pneumonia, bacterial invasion of bone, and in the treatment of burns as well as boils and carbuncles. It became abundantly clear that the discovery of the first antibiotic was perhaps the greatest single victory ever achieved by science over infectious disease.

  For this epoch-making discovery the three principals – Fleming, Florey and Chain – received the Nobel Prize in 1945 with the citation: ‘For the discovery of penicillin and its therapeutic effect for the cure of different infectious maladies.’

  Source: Sarah R. Riedman and Elton T. Gustafson, Portraits of Nobel Laureates in Medicine and Physiology, London, New York, Toronto, Abelard-Schuman, 1963.

  In the Black Squash Court: The First Atomic Pile

  The director of the team that built the world’s first atomic pile was the Italian physicist Enrico Fermi, who had quit Fascist Italy in 1938. In the same year he had been awarded the Nobel Prize for developing the technique of bombarding uranium atoms with neutrons. Following on this work, Otto Hahn and Fritz Strassman in Berlin had found that among the fragments obtained when uranium atoms were bombarded were atoms of barium, which has an atomic weight approximately half that of uranium. It was their colleague the Austrian Lise Meitner and her nephew Otto Frisch who realized that what had taken place was atomic fission – the uranium atom splitting to produce two of barium. Since a uranium atom undergoing fission would also emit neutrons, it occurred to Fermi and others that a chain reaction might occur – the emitted neutrons hitting other uranium atoms and splitting them, thus emitting other neutrons which would hit and split other atoms, and so on, a process that would release a huge amount of energy. The function of an atomic pile is to induce and control such a reaction. Fermi’s team on the project included Herbert Anderson, the Hungarian Leo Szilard, and the Canadian Walter H. Zinn. This account is from his wife Laura Fermi’s book, Atoms in the Family, 1955.

  The operation of the atomic pile was the result of almost four years of sustained work, which started when discovery of uranium fission became known, arousing enormous interest among physicists.

  Experiments at Columbia University and at other unive
rsities in the United States had confirmed Enrico’s hypothesis that neutrons would be emitted in the process of fission. Consequently, a chain reaction appeared possible in theory. To achieve it in practice seemed a vague and distant possibility. The odds against it were so great that only the small group of stubborn physicists at Columbia pursued work in that direction. At once they were faced with two sets of difficulties.

  The first lay in the fact that neutrons emitted in the process of uranium fission were too fast to be effective atomic bullets and to cause fission in uranium. The second difficulty was due to loss of neutrons: under normal circumstances most of the neutrons produced in fission escaped into the air or were absorbed by matter before they had a chance of acting as uranium splitters. Too few produced fission to cause a chain reaction.

  Neutrons would have to be slowed down and their losses reduced by a large factory if a chain reaction was to be achieved. Was this feasible?