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Alexander Fleming

Sir Alexander Fleming FRSE, FRS, FRCS(Eng) (6 August 1881 – 11 March 1955) was a Scottish biologist and pharmacologist. He wrote many articles on bacteriology, immunology, HP Envy 17-1012nr Battery

and chemotherapy. His best-known discoveries are the enzyme lysozyme in 1923 and the antibiotic substance penicillin from the mould Penicillium notatum in 1928, for which he shared the Nobel Prize in Physiology or Medicine in 1945 with Howard Florey and Ernst Boris Chain.[1]HP Envy 17-1013tx Battery

In 1999, Time magazine named Fleming one of the 100 Most Important People of the 20th Century for his discovery[2] ofpenicillin, and stated: HP Envy 17-1017tx Battery

It was a discovery that would change the course of history. The active ingredient in that mould, which Fleming named penicillin, turned out to be an infection-fighting agent of enormous potency. When it was finally recognized for what it was, HP Envy 17-1050ea Battery

the most efficacious life-saving drug in the world, penicillin would alter forever the treatment of bacterial infections. By the middle of the century, Fleming's discovery had spawned a huge pharmaceutical industry, churning out synthetic penicillins that would conquer some of mankind's most ancient scourges, including syphilis, gangrene andtuberculosis.[3]HP Envy 17-1050eb Battery

EARLY LIFE

Fleming was born on 6 August 1881 at Lochfield , a farm near Darvel, in Ayrshire, Scotland. He was the third of the four children of farmer Hugh Fleming (1816–1888) from his second marriage to Grace Stirling Morton (1848–1928), the daughter of a neighbouring farmer. HP Envy 17-1085eo Battery

Hugh Fleming had four surviving children from his first marriage. He was 59 at the time of his second marriage, and died when Alexander (known as Alec) was seven. HP Envy 17-1050ep Battery

Fleming went to Loudoun Moor School and Darvel School, and earned a two-year scholarship to Kilmarnock Academy before moving to London, where he attended theRoyal Polytechnic Institution.[4] After working in a shipping office for four years, the twenty-year-old Fleming inherited some money from an uncle, John Fleming. His elder brother, HP Envy 17-1090ca Battery

Tom, was already a physician and suggested to his younger sibling that he follow the same career, and so in 1903, the younger Alexander enrolled at St Mary's Hospital Medical School in Paddington. He qualified MBBS from the school with distinction in 1906. HP Envy 17-1090ez Battery

Fleming had been a private in the London Scottish Regiment of the Volunteer Force since 1900,[1] and had been a member of the rifle club at the medical school. The captain of the club, wishing to retain Fleming in the team suggested that he join the research department at St Mary's, HP Envy 17-1100 Battery

where he became assistant bacteriologist to Sir Almroth Wright, a pioneer in vaccine therapy and immunology. He gained a BSc with Gold Medal in 1908, and became a lecturer at St Mary's until 1914. On 23 December 1915, Fleming married a trained nurse, Sarah Marion McElroy of Killala, County Mayo, Ireland. HP Envy 17-1103tx Battery

Fleming served throughout World War I as a captain in the Royal Army Medical Corps, and was Mentioned in Dispatches. He and many of his colleagues worked in battlefield hospitals at the Western Front in France. In 1918 he returned to St Mary's Hospital, where he was elected Professor of Bacteriology of theUniversity of London in 1928. HP Envy 17-1104tx Battery

Following World War I, Fleming actively searched for anti-bacterial agents, having witnessed the death of many soldiers from sepsis resulting from infectedwounds. Antiseptics killed the patients' immunological defences more effectively than they killed the invading bacteria. HP Envy 17-1190ea Battery

 In an article he submitted for the medical journal The Lancet during World War I, Fleming described an ingenious experiment, which he was able to conduct as a result of his own glass blowing skills, in which he explained why antiseptics were killing more soldiers than infection itself during World War I. HP Envy 17-1200 Battery

Antiseptics worked well on the surface, but deep wounds tended to shelter anaerobic bacteria from the antiseptic agent, HP Envy 17-2001tx Battery

and antiseptics seemed to remove beneficial agents produced that protected the patients in these cases at least as well as they removed bacteria, and did nothing to remove the bacteria that were out of reach. Sir Almroth Wright strongly supported Fleming's findings, but despite this, most army physicians over the course of the war continued to use antiseptics even in cases where this worsened the condition of the patients. HP Envy 17-2002xx Battery

 

Accidental discovery

"When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer," Fleming would later say, "But I suppose that was exactly what I did."[2][5]HP Envy 17-2003ef Battery

 

By 1927, Fleming was investigating the properties of staphylococci. He was already well-known from his earlier work, and had developed a reputation as a brilliant researcher, but his laboratory was often untidy. On 3 September 1928, HP Envy 17-2009tx Battery

Fleming returned to his laboratory having spent August on holiday with his family. Before leaving, he had stacked all his cultures of staphylococci on a bench in a corner of his laboratory. On returning, Fleming noticed that one culture was contaminated with a fungus, HP Envy 17-2012tx Battery

and that the colonies of staphylococci that had immediately surrounded it had been destroyed, whereas other colonies farther away were normal. Fleming showed the contaminated culture to his former assistant Merlin Price, who reminded him, HP Envy 17-2013tx Battery

"That's how you discovered lysozyme."[6] Fleming grew the mould in a pure culture and found that it produced a substance that killed a number of disease-causing bacteria. He identified the mould as being from the Penicillium genus, and, after some months of calling it "mould juice", named the substance it released penicillin on 7 March 1929.[7]HP Envy 17-2014tx Battery

He investigated its positive anti-bacterial effect on many organisms, and noticed that it affected bacteria such as staphylococci and many other Gram-positivepathogens that cause scarlet fever, pneumonia, meningitis and diphtheria, HP Envy 17-2070nr Battery

but not typhoid fever or paratyphoid fever, which are caused by Gram-negativebacteria, for which he was seeking a cure at the time. It also affected Neisseria gonorrhoeae, which causes gonorrhoea although this bacterium is Gram-negative. HP Envy 17-2090eg Battery

Fleming published his discovery in 1929, in the British Journal of Experimental Pathology,[8] but little attention was paid to his article. Fleming continued his investigations, but found that cultivating penicillium was quite difficult, and that after having grown the mould, HP Envy 17-2090nr 3D Battery

it was even more difficult to isolate the antibiotic agent. Fleming's impression was that because of the problem of producing it in quantity, and because its action appeared to be rather slow, penicillin would not be important in treating infection. HP Envy 17-2093eg Battery

Fleming also became convinced that penicillin would not last long enough in the human body (in vivo) to kill bacteria effectively. Many clinical tests were inconclusive, probably because it had been used as a surface antiseptic. In the 1930s, HP Envy 17-2096eg Battery

Fleming’s trials occasionally showed more promise,[9] and he continued, until 1940, to try to interest a chemist skilled enough to further refine usable penicillin. Fleming finally abandoned penicillin, and not long after he did, HP Envy 17 Notebook PC Battery

Howard Florey and Ernst Boris Chain at the Radcliffe Infirmary in Oxford took up researching and mass-producing it, with funds from the U.S. and British governments. They started mass production after the bombing of Pearl Harbor. When D-Day arrived, they had made enough penicillin to treat all the wounded Allied forces. HP Envy 17t-1000 Battery

Purification and stabilisation

Ernst Boris Chain and Edward Abraham worked out how to isolate and concentrate penicillin. Abraham was the first to propose the correct structure of penicillin.[10][11] HP Envy 17t-2000 CTO 3D Battery

Shortly after the team published its first results in 1940, Fleming telephonedHoward Florey, Chain's head of department, to say that he would be visiting within the next few days. When Chain heard that he was coming, he remarked "Good God! I thought he was dead." HP Envy 17t-2000 CTO Battery

 

Norman Heatley suggested transferring the active ingredient of penicillin back into water by changing its acidity. This produced enough of the drug to begin testing on animals. There were many more people involved in the Oxford team, and at one point the entire Dunn School was involved in its production. HP Envy 17t Battery

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After the team had developed a method of purifying penicillin to an effective first stable form in 1940, several clinical trials ensued, and their amazing success inspired the team to develop methods for mass production and mass distribution in 1945. HP G42-100 Battery

 

Fleming was modest about his part in the development of penicillin, describing his fame as the "Fleming Myth" and he praised Florey and Chain for transforming the laboratory curiosity into a practical drug. Fleming was the first to discover the properties of the active substance, HP G42-101XX Battery

giving him the privilege of naming it: penicillin. He also kept, grew and distributed the original mould for twelve years, and continued until 1940 to try to get help from any chemist who had enough skill to make penicillin. But Sir Henry Harris said in 1998: HP G42-154CA Battery

"Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin."[12]HP G42-164LA Battery

Fleming's accidental discovery and isolation of penicillin in September 1928 marks the start of modern antibiotics. Before that, several scientists had published or pointed out that mould or penicillium sp. were able to inhibit bacterial growth, HP G42-240LA Battery

and even to cure bacterial infections in animal (Ernest Duchesne in 1897 in his thesis "Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes", HP G42-250LA Battery

or also Clodomiro Picado Twight whose work at Institut Pasteur in 1923 on the inhibiting action of fungi of the "Penicillin sp" genre in the growth of staphylococci drew little interest from the direction of the Institut at the time). HP G42-301NR Battery

Fleming was the first to push these studies further by isolating the penicillin, and by being motivated enough to promote his discovery at a larger scale. Fleming also discovered very early that bacteria developed antibiotic resistance whenever too little penicillin was used or when it was used for too short a period. HP G42-303DX Battery

Almroth Wright had predicted antibiotic resistance even before it was noticed during experiments. Fleming cautioned about the use of penicillin in his many speeches around the world. HP G42-352TU Battery

He cautioned not to use penicillin unless there was a properly diagnosed reason for it to be used, and that if it were used, never to use too little, or for too short a period, since these are the circumstances under which bacterial resistance to antibiotics develops. HP G42-328CA Battery

PERSONAL LIFE

The popular story[13] of Winston Churchill's father paying for Fleming's education after Fleming's father saved young Winstonfrom death is false. According to the biography, Penicillin Man: Alexander Fleming and the Antibiotic Revolution by Kevin Brown, Alexander Fleming, HP G42-352TX Battery

in a letter[14] to his friend and colleague Andre Gratia,[15] described this as "A wondrous fable." Nor did he save Winston Churchill himself during World War II. Churchill was saved by Lord Moran, using sulphonamides, since he had no experience with penicillin, HP G42-360TU Battery

when Churchill fell ill in Carthage in Tunisia in 1943. TheDaily Telegraph and the Morning Post on 21 December 1943 wrote that he had been saved by penicillin. He was saved by the new sulphonamide drug, Sulphapyridine, HP G42-360TX Battery

known at the time under the research code M&B 693, discovered and produced by May & Baker Ltd, Dagenham, Essex – a subsidiary of the French group Rhône-Poulenc. In a subsequent radio broadcast, Churchill referred to the new drug as "This admirable M&B."[16] HP G42-361TU Battery

It is highly probable that the correct information about the sulphonamide did not reach the newspapers because, since the original sulphonamide antibacterial, Prontosil, had been a discovery by the German laboratory Bayer, and as Britain was at war with Germany at the time, it was thought better to raise British morale by associating Churchill's cure with the British discovery, penicillin. HP G42-361TX Battery

Fleming's first wife, Sarah, died in 1949. Their only child, Robert Fleming, became a general medical practitioner. After Sarah's death, Fleming married Dr.Amalia Koutsouri-Vourekas, a Greek colleague at St. Mary's, on 9 April 1953; she died in 1986.[17]HP G42-364TX Battery

His discovery of penicillin had changed the world of modern medicine by introducing the age of useful antibiotics; penicillin has saved, and is still saving, millions of people around the world.[19]HP G42-365TX Battery

 

The laboratory at St Mary's Hospital where Fleming discovered penicillin is home to the Fleming Museum, a popular London attraction. His alma mater, St Mary's Hospital Medical School, merged with Imperial College London in 1988. The Sir Alexander Fleming Building on the South Kensington campus was opened in 1998 and is now one of the main preclinical teaching sites of the Imperial College School of Medicine. HP G42-366TU Battery

 

His other alma mater, the Royal Polytechnic Institution (now the University of Westminster) has named one of its student halls of residence Alexander Fleming House, which is near to Old Street. HP G42-366TX Battery

 

Penicillin

Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from Penicillium fungi.[1] They includepenicillin G, procaine penicillin, benzathine penicillin, and penicillin V. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such assyphilis, HP G42-367CL Battery

and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are β-lactam antibiotics and are used in the treatment of bacterialinfections caused by susceptible, usually Gram-positive, organisms. HP G42-367TU Battery

HP G42-368TX Battery

 

The term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G), procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillin V). HP G42-369TU Battery

 

Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period. Phenoxymethylpenicillin is less active against Gram-negative bacteria than benzylpenicillin.[2][3] Benzylpenicillin, procaine penicillin and benzathine penicillin are given by injection (parenterally), but phenoxymethylpenicillin is given orally. HP G42-370TU Battery

 

Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation. HP G42-370TX Battery

The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, HP G42-371TU Battery

 which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due toosmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, HP G42-372TU Battery

which further digest the bacteria's existing peptidoglycan. This imbalance between cell wall production and degradation is responsible for the rapid cell-killing action of this class of drugs, even in the absence of cell division. In addition, HP G42-372TX Battery

the relatively small size of the penicillin molecule allows it to penetrate deeply into the cell wall, affecting its entire depth. This is in contrast to the other major class of anitbiotics that inhibit cell wall synthesis, the glycopeptideantibiotics (which includes vancomycin and teicoplanin). HP G42-375TX Battery

Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin.[citation needed]HP G42-378TX Battery

Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms. HP G42-380TX Battery

Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. HP G42-381TX Battery

In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of theevolution of plastid division in land plants.[5]HP G42-382TX Battery

The term "penam" is used to describe the core skeleton of a member of the penicillin antibiotics. This skeleton has the molecular formula R-C9H11N2O4S, where R is a variable side chain. HP G42-383TX Battery

Normal penicillin has a molecular weight of 313[6] to 334[7][8] g/mol (latter for penicillin G). Penicillin types with additional molecular groups attached may have a molar mass around 500 g/mol. For example, cloxacillin has a molar mass of 476 g/mol and dicloxacillin has a molar mass of 492 g/mol.[9]HP G42-384TX Battery

The first step is the condensation of three amino acids — L-α-aminoadipic acid, L-cysteine, L-valine into atripeptide.[10][11][12] Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine.[13][14]HP G42-385TX Battery

 The condensed tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), a nonribosomal peptide synthetase or NRPS. HP G42-386TX Battery

The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC.[10][11] Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.[13]HP G42-387TX Battery

The final step is an transamidation by isopenicillin N N-acyltransferase, in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.[10]HP G42-388TX Battery

Penicillin is a secondary metabolite of certain species of Penicillium and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin. HP G42-394TX Battery

The by-product, l-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production. HP G42-397TX Battery

The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: Glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled. HP G42-398TX Battery

The biotechnological method of directed evolution has been applied to produce by mutation a large number of Penicilliumstrains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR.。Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA. HP G42 Battery

The discovery of penicillin is attributed to Scottish scientist and Nobel laureate Alexander Fleming in 1928.[15] He showed that, if Penicillium notatum were grown in the appropriate substrate, it would exude a substance with antibiotic properties, which he dubbed penicilliHP G42T-200 CTO Battery

This serendipitous observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate Howard Walter Florey, together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley. HP G42t-300 CTO Battery

 

However, several others reported the bacteriostatic effects of Penicillium earlier than Fleming. The use of bread with a blue mould (presumed to be Penicillium) as a means of treating suppurating wounds was a staple of folk medicine in Europe since the Middle Ages.[citation needed]HP G42t Battery

 

The first published reference appears in the publication of the Royal Society in 1875, by John Tyndall.[16] Joaquim Monteiro Caminhoá, Professor of Botany and Zoology of the Faculty of Medicine of Rio de Janeiro, Brazil, also recognised the antibiotic activity of Penicillium and other fungi in 1877. In his book, "Elements of General and Medical Botany" (under a section titled 'Useful fungi, harmful and curious'), he stated: HP G42t Notebook PC Series Battery

 

O bolor (Penicillium infestansPenicillium glaucum, fig 1680, Ascophora e tantos outros) é util porque nutre-se decompondo e destruindo as materias organicas em putrefacção, e de modo que o cheiro infecto não se produz, em via de regra, ou produz-se em proporções infinitamente menores. HP G56-100SA Battery

 [Translation: "The mould (Penicillium infestansPenicillium glaucum, figure 1680, Ascophora and many others) is useful because it feeds on decaying organic matter and destroys putrifaction so that, as a rule, the odour of infection does not occur, or is produced in infinitely smaller amounts."][17]HP G56-105SA Battery

 

In 1895, Vincenzo Tiberio, physician of the University of Naples published a research about a mold ( Penicillium ) in a water well that had a antibacterial action.[18][19]HP G56-106EA Battery

 

Ernest Duchesne documented it in an 1897 paper, which was not accepted by the Institut Pasteur because of his youth. In March 2000, doctors at the San Juan de Dios Hospital in San José, Costa Rica, published the manuscripts of the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887–1944). HP G56-106SA Battery

They reported Picado's observations on the inhibitory actions of fungi of the genus Penicillium between 1915 and 1927. Picado reported his discovery to theParis Academy of Sciences, yet did not patent it, even though his investigations started years before Fleming's. Joseph Lister was experimenting with Penicillumin 1871 for his aseptic surgery. He found that it weakened the microbes, but then he dismissed the fungi. HP G56-107SA Battery

 

These early investigations did not lead to the use of antibiotics to treat infection because they took place in obscure circumstances, and the idea that infections were caused by transmissible agents was not widely accepted at the time. HP G56-108SA Battery

Sterilization measures had been shown to limit the outbreak and spread of disease; however, the mechanism of transmission of disease by parasites, bacteria, viruses and other agents was unknown. In the late 19th century, HP G56-109SA Battery

 

 there was increasing knowledge of the mechanisms by which living organisms become infected, how they manage infection once it has begun and, most importantly in the case of penicillin, the effect that natural and man-made agents could have on the progress of infection. HP G56-112SA Battery

Fleming recounted that the date of his discovery of penicillin was on the morning of Friday, September 28, 1928.[20] It was a fortuitous accident: in his laboratory in the basement of St. Mary's Hospital in London (now part of Imperial College), HP G56-130SA Battery

 Fleming noticed a Petri dish containing Staphylococcus plate culture he mistakenly left open, was contaminated by blue-green mould, which formed a visible growth. There was a halo of inhibited bacterial growth around the mould. HP G56 Battery

Fleming concluded that the mould released a substance that repressed the growth and lysing the bacteria. He grew a pure culture and discovered it was aPenicillium mould, now known to be Penicillium notatum. Charles Thom, HP G62-100 Battery

an American specialist working at the U.S. Department of Agriculture, was the acknowledged expert, and Fleming referred the matter to him. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mould. HP G62-100EB Battery

Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, HP G62-100EE Battery

being highly potent with minimal toxicity compared to antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now Haemophilus influenzae).[21] HP G62-100EJ Battery

After further experiments, Fleming was convinced penicillin could not last long enough in the human body to kill pathogenic bacteria, and stopped studying it after 1931. He restarted clinical trials in 1934, and continued to try to get someone to purify it until 1940.[22]HP G62-100SL Battery

In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use penicillin to treat sycosis barbae, eruptions in beard follicles, but was unsuccessful, probably because the drug did not penetrate the skin deeply enough. HP G62-101TU Battery

Moving on toophthalmia neonatorum, a gonococcal infection in infants, he achieved the first recorded cure with penicillin, on November 25, 1930. He then cured four additional patients (one adult and three infants) of eye infections, failing to cure a fifth.[23]HP G62-101XX Battery

In 1939, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Boris Chain, Arthur Duncan Gardner,Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, HP G62-103XX Battery

 University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed because of insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved it harmless and effective on mice.[24]HP G62-104SA Battery

 

Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford, England. These trials continue to be cited by some sources as the first cures using penicillin, though the Paine trials took place earlier.[23] On March 14, 1942, John Bumstead and Orvan Hess saved a dying patient's life using penicillin.[25][26]HP G62-105SA Battery

MASS PRODUCTION

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in 1945[chronology citation needed]. Penicillin has since become the most widely used antibiotic to date, and is still used for many Gram-positive bacterial infections. HP G62-106SA Battery

A team of Oxford research scientists led by Australian Howard Florey and including Ernst Boris Chain and Norman Heatley devised a method of mass-producing the drug. Florey and Chain shared the 1945 Nobel Prize in Medicine with Fleming for their work. After World War II, HP G62-107SA Battery

Australia was the first country to make the drug available for civilian use. Chemist John C. Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. HP G62-110ED Battery

The challenge of mass-producing this drug was daunting. On March 14, 1942, the first patient was treated for streptococcal septicemia with U.S.-made penicillin produced by Merck & Co.[27] Half of the total supply produced at the time was used on that one patient. HP G62-110EE Battery

By June 1942, there was just enough U.S. penicillin available to treat ten patients.[28] In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe.[29] HP G62-110EO Battery

A mouldy cantaloupe in a Peoria, Illinois, market in 1943 was found to contain the best and highest-quality penicillin after a worldwide search.[30] The discovery of the cantaloupe, and the results of fermentation research on corn steep liquor at the Northern Regional Research Laboratory at Peoria, Illinois, HP G62-110EY Battery

allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. Large-scale production resulted from the development of deep-tank fermentation by chemical engineer Margaret Hutchinson Rousseau.[31]HP G62-110SO Battery

 As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.[29]HP G62-110SA Battery

G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin.[32] During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%–15% of lives.[citation needed] HP G62-110SS Battery

Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. HP G62-110SW Battery

Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.[33] HP G62-111EE Battery

This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. HP G62-112EE Battery

The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. HP G62-112SO Battery

Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.[33] Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.[4]HP G62-113SO Battery

UNETHICAL EXPERIMENTATION

In a 1946 to 1948 study in Guatemala, U.S. researchers used prostitutes to infect prison inmates, insane asylum patients, and Guatemalan soldiers with syphilis and other sexually transmitted diseases (STDs), to test the effectiveness of penicillin in treating such diseases. HP G62-115SE Battery

They later tried infecting people with "direct inoculations made from syphilis bacteria poured into the men's penises and on forearms and faces that were slightly abraded ... or in a few cases through spinal punctures".[34]HP G62-115SO Battery

 Approximately 1300 people were infected as part of the study (including orphaned children). The study was sponsored by the Public Health Service, the National Institutes of Health and the Pan American Health Sanitary Bureau (now the World Health Organization's Pan American Health Organization) and the Guatemalan government. HP G62-117SO Battery

The team was led by John Charles Cutler, who later participated in the Tuskegee syphilis experiments. Cutler chose to do the study in Guatemala because he would not have been permitted to do it in the United States.[35][36][37][38] The Presidential Commission for the Study of Bioethical Issues determined that 83 people died; however, it was not possible to determine whether the experiments were the direct cause of death.[39]HP G62-118EO Battery

 

DEVELOPMENTS FROM PENICILLIN

The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. HP G62-120EC Battery

The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance). HP G62-120EE Battery

 

The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, HP G62-120EG Battery

 dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged. HP G62-120EH Battery

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, thecarbapenems and, most important, the cephalosporins, still retain it at the center of their structures.[40]HP G62-120EK Battery

Norman Heatley

Norman George Heatley (10 January 1911 – 5 January 2004) was a member of the team of Oxford University scientists who developed penicillin. HP G62-120EL Battery

He was born in Woodbridge, Suffolk, and as a boy was an enthusiastic sailor of a small boat on the River Deben; an experience which gave him a lifelong love of sailing. He attended school in Folkestone and Tonbridge, HP G62-120EP Battery

then went on to St John's College, Cambridge, where he studied Natural Sciences, graduating in 1933. His doctoral research in Cambridge led to a PhD in 1936, and he then moved to Oxford where he became a fellow of Lincoln College and joined a team working underHoward Florey, which also included Ernst Chain. HP G62-120EQ Battery

Alexander Fleming had first discovered penicillin by accident in 1928, but at that time believed it had little application. When Florey and his team recognised the potential of the discovery for combating bacterial infection, they faced the problem of how to manufacture penicillin in sufficient quantities to be of use. HP G62-120ER Battery

Heatley, although the junior member of the team, possessed a natural gift for ingenuity and invention. It was he who suggested transferring the active ingredient of penicillin back into water by changing its acidity, this would purify the penicillin. HP G62-120ES Battery

Heatley recorded these trials, carried out on eight mice in May 1940, in his diary:

"After supper with some friends, I returned to the lab and met the professor to give a final dose of penicillin to two of the mice. The 'controls' were looking very sick, but the two treated mice seemed very well. I stayed at the lab until 3.45 a.m., by which time all four control animals were dead." HP G62-120ET Battery

On returning home, he realised that in haste and darkness, he had put his underpants on back to front, and noted this in his diary too, adding "It really looks as if penicillin may be of practical importance."[1]HP G62-120EY Battery

In order to conduct tests on human patients, even more of the drug had to be produced, and again it was Heatley who realised that the most effective vessel for this purpose was something like the porcelain bedpans in use at the Radcliffe Infirmary. HP G62-120SE Battery

These were in short supply because of wartime, so Heatley designed a modified version which was manufactured in the Potteries. With the help of these, the Oxford laboratory became the first penicillin factory, and subsequent tests on human beings proved the efficacy of the new treatment. HP G62-120SL Battery

Even so, it was very difficult to produce enough for sustained treatment, Penicillin was tried on a local policeman, he had a sore on his mouth about a month previously and the infection had spread to his scalp. He'd had abscess there, HP G62-120SS Battery

it spread to both his eyes and one had to be removed. He had abscesses open on his arm, he had abscesses on his lung - he was on his way towards death from the terrible infection. Heatley, Florey, Chain and the rest of the Oxford team, tried it on the dying policeman. HP G62-120SW Battery

This was one of the first tests of penicillin, each day the penicillin was extracted from the policeman's urine and used on him again. It had taken four days for him to improve, but on the fifth day there was not enough penicillin to be extracted. HP G62-121EE Battery

Eventually Heatley and Florey travelled to the United States in 1941 because they wanted to produce about one kilogram of pure penicillin, and persuaded a laboratory in Peoria, Illinois, to develop larger scale manufacturing. HP G62-125EK Battery

In Peoria, Heatley was assigned to work with Dr. A. J. Moyer. Moyer suggested adding corn-steep liquor, a by-product of starch extraction, to the growth medium. With this and other subtle changes, such as using lactose in place of glucose, HP G62-125EL Battery

they were able to push up yields of penicillin to 20 units per ml. But their cooperation had become one-sided. Heatley noted that "Moyer had begun not telling me what he was doing." Florey returned to Oxford that September, but Heatley stayed on in Peoria until December, HP G62-125EV Battery

then for the next six months he worked at Merck & Co. Inc. in Rahway, New Jersey. In July 1942 he returned to Oxford, and was soon to learn why Moyer had become so secretive. When he published their research results he omitted Heatley's name from the paper, HP G62-125SL Battery

despite an original contract which stipulated that any publications should be jointly authored. Fifty years on, Heatley confessed that he was amused, rather than upset, by Moyer's duplicity. Later he was to learn that Moyer had a good reason for taking all the credit to himself. HP G62-130 Battery

To have acknowledged Heatley's part of the work would have made it difficult to apply for patents with himself as sole inventor, which is what he did.

Without Fleming, no Chain or Florey; without Florey, no Heatley; without Heatley, no penicillin. HP G62-130EG Battery

Yet while Fleming, Florey and Chain all received the Nobel prize for their work, Heatley's contribution was not fully recognised for another 50 years. It was only in 1990 that he was awarded the unusual distinction of an honorary Doctorate of Medicine from Oxford University, the first given to a non-medic in Oxford's 800-year history.[2]HP G62-130EK Battery

Heatley died on 5 January 2004 at his care home, 12 Oxford Road, Marston, Oxfordshire, which now bears a blue plaque in his honour.[3] He was buried in abiodegradable coffin after a funeral service at St Nicholas's Church, Marston, on 15 January. He was survived by his wife, Mercy, and four children. HP G62-130ET Battery

Howard Florey

Howard Walter Florey, Baron Florey OM FRS (24 September 1898 – 21 February 1968) was an Australian pharmacologist andpathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Sir Ernst Boris Chain and Sir Alexander Fleming for his role in the making of penicillin. HP G62-130EV Battery

Florey's discoveries are estimated to have saved over 6 million lives, in Australia.[1] Florey is regarded by the Australian scientific and medical community as one of its greatest scientists. Sir Robert Menzies, Australia's longest-serving Prime Minister, said that "in terms of world well-being, Florey was the most important man ever born in Australia".[2]HP G62-130SD Battery

Born the youngest of five children in Adelaide, South Australia, Howard Florey was educated at St Peter's College, Adelaide, where he was a brilliant student and junior sportsman. He studied medicine at the University of Adelaide from 1917 to 1921. HP G62-130SL Battery

At the university he met Ethel Reed, another medical student, who became both his wife and his research colleague. A Rhodes Scholar, he continued his studies at Magdalen College, Oxford, receiving the degrees of BA and MA. In 1926 he was elected to a fellowship at Gonville and Caius College, Cambridge, and a year later he received the degree ofPhD from the University of Cambridge. HP G62-134CA Battery

After periods in the United States and at Cambridge, he was appointed to the Joseph Hunter Chair of Pathology at theUniversity of Sheffield in 1931. HP G62-135EV Battery

In 1935 he returned to Oxford, as Professor of Pathology and Fellow of Lincoln College, leading a team of researchers. In 1938, working with Ernst Boris Chain and Norman Heatley, he read Alexander Fleming's paper discussing the antibacterial effects of Penicillium notatum mould. HP G62-140EL Battery

In 1941, they treated their first patient, Albert Alexander, who had been scratched by a rose thorn. His whole face, eyes, scalp were swollen, and he had an eye removed to relieve some of the pain. Within a day of being given penicillin, HP G62-140EQ Battery

he started recovering. However they did not have enough penicillin to help him to full recovery, he relapsed, and died. Because of this experience, they changed their focus to children, who did not need such large quantities of penicillin. HP G62-140ES Battery

 

Florey's research team investigated the large-scale production of the mould and efficient extraction of the active ingredient, succeeding to the point where, by 1945, penicillin production was an industrial process for the Allies in World War II. However, Florey held that the project was originally driven by scientific interests, and that the medicinal discovery was a bonus: HP G62-140ET Battery

Florey shared the Nobel Prize in Physiology or Medicine in 1945 with Ernst Boris Chain and Alexander Fleming. Fleming first observed the antibiotic properties of the mould that makes penicillin, but it was Chain and Florey who developed it into a useful treatment.[4]HP G62-140SF Battery

While he considered himself to be an agnostic, he was not aggressive in his disbelief.[5]

He was openly concerned about the population explosion resulting from improving healthcare, and was a staunch believer in contraception.[3]HP G62-140SS Battery

After the death of his wife Ethel, he married his long-time colleague and research assistant Dr. Margaret Jennings in 1967. He died of a heart attack in 1968 and was honoured with a memorial service at Westminster Abbey, London. HP G62-140US Battery

Florey was appointed a Knight Bachelor in 1944.[6]

He was awarded the Lister Medal in 1945 for his contributions to surgical science.[7] The corresponding Lister Oration, given at the Royal College of Surgeons of England later that year, was titled "Use of Micro-organisms for Therapeutic Purposes".[8]HP G62-143CL Battery

Florey was elected president of the Royal Society in 1958 In 1962, Florey became Provost of The Queen's College, Oxford. During his term as Provost, the college built a new accommodation block, named the Florey Building in his honour. The building was designed by the British architect Sir James Stirling. HP G62-144DX Battery

He was made a life peer in 1965 as Baron Florey, of Adelaide in the State of South Australia and Commonwealth of Australia and of Marston in the County of Oxford. This was a higher honour than the knighthood awarded to penicillin's discoverer, nr-battery.html">HP G62-145NR Battery

Sir Alexander Fleming, and it recognised the monumental work Florey did in making penicillin available in sufficient quantities to save millions of lives in the war, despite Fleming's doubts that this was feasible. HP G62-147NR Battery

Florey was Chancellor of the Australian National University from 1965 until his death in 1968.

The lecture theater at the John Curtin School of Medical Research was named for him during his tenure at the Australian National University. HP G62-149WM Battery

Alan Mathison Turing

Alan Mathison Turing, was an English mathematician, logician,cryptanalyst, and computer scientist. He was highly influential in the development of computer science, providing a formalisation of the concepts of "algorithm" and "computation" with the Turing machine, HP G62-150EE Battery

which played a significant role in the creation of the modern computer.[1][2] Turing is widely considered to be the father of computer science and artificial intelligence.[3]HP G62-150EF Battery

During the Second World War, Turing worked for the Government Code and Cypher School (GCCS) at Bletchley Park, Britain'scodebreaking centre. HP G62-150EQ Battery

For a time he was head of Hut 8, the section responsible for German naval cryptanalysis. He devised a number of techniques for breaking German ciphers, including the method of the bombe, an electromechanical machine that could find settings for the Enigma machine. HP G62-150ET Battery

After the war he worked at the National Physical Laboratory, where he created one of the first designs for a stored-program computer, the ACE. In 1948 Turing joined Max Newman's Computing Laboratory at Manchester University, HP G62-150EV Battery

where he assisted in the development of the Manchester computers[4] and became interested in mathematical biology. He wrote a paper on the chemical basis of morphogenesis,[5] and he predicted oscillating chemical reactions such as the Belousov–Zhabotinsky reaction, which were first observed in the 1960s. HP G62-150SE Battery

Turing's homosexuality resulted in a criminal prosecution in 1952, when homosexual acts were still illegal in the United Kingdom. He accepted treatment with female hormones (chemical castration) as an alternative to prison. He died in 1954, HP G62-150SF Battery

just over two weeks before his 42nd birthday, from cyanide poisoning. An inquest determined it was suicide; his mother and some others believed his death was accidental. On 10 September 2009, following an Internet campaign, British Prime MinisterGordon Brown made an official public apology on behalf of the British government for the way in which Turing was treated after the war.[6]HP G62-150SL Battery

Turing was conceived at Chhatrapur, Orissa, then part of British India.[7][8] His father, Julius Mathison Turing, was a member of the Indian Civil Service. He and his wife Ethel Sara Stoney (1881–1976), daughter of Edward Waller Stoney, HP G62-153CA Battery

chief engineer of the Madras Railways, wanted their children to be brought up in England, so they returned to Maida Vale,[9]London, where Turing was born on 23 June 1912, as recorded by a blue plaque on the outside of the house of his birth,[10]HP G62-154CA Battery

later the Colonnade Hotel.[7][11] He had an elder brother, John. His father's civil service commission was still active, and during Turing's childhood years his parents travelled between Hastings, England[12] and India, leaving their two sons to stay with a retired Army couple. Very early in life, Turing showed signs of the genius he was later to display prominently.[13]HP G62-165SL Battery

His parents enrolled him at St Michael's, a day school at 20 Charles Road, St Leonards-on-Sea, at the age of six. The headmistress recognised his talent early on, as did many of his subsequent educators. In 1926, at the age of 14, he went on to Sherborne School, HP G62-166SB Battery

a famous independent school in the market town ofSherborne in Dorset. His first day of term coincided with the 1926 General Strike in Britain, but so determined was he to attend his first day that he rode his bicycle unaccompanied more than 60 miles (97 km) from Southampton to school, stopping overnight at an inn.[14]HP G62-200XX Battery

Turing's natural inclination toward mathematics and science did not earn him respect with some of the teachers at Sherborne, whose definition of education placed more emphasis on the classics. His headmaster wrote to his parents: HP G62-201XX Battery

"I hope he will not fall between two stools. If he is to stay at public school, he must aim at becoming educated. If he is to be solely aScientific Specialist, he is wasting his time at a public school".[15] Despite this, Turing continued to show remarkable ability in the studies he loved, HP G62-219WM Battery

solving advanced problems in 1927 without having even studied elementary calculus. In 1928, aged 16, Turing encountered Albert Einstein's work; not only did he grasp it, but he extrapolated Einstein's questioning ofNewton's laws of motion from a text in which this was never made explicit.[16]HP G62-251XX Battery

Turing's hopes and ambitions at school were raised by the close friendship he developed with a slightly older fellow student, Christopher Morcom, who was Turing's first love interest. Morcom died suddenly on 13 February 1930,[17] only a few weeks into their last term at Sherborne, HP G62-400 Battery

from complications of bovine tuberculosis, contracted after drinking infected cow's milk as a boy.[18] Turing's religious faith was shattered and he became an atheist. He adopted the conviction that all phenomena, including the workings of the human brain, must be materialistic,[19] but he still believed in the survival of the spirit after death.[20]HP G62-450SA Battery

Turing was stockily built, had a high-pitched voice, and was talkative, witty, and somewhat donnish.[21] He showed many of the characteristics that are indicative of Asperger syndrome.[22]HP G62-451SA Battery

University and work on computability

After Sherborne, Turing went to study at King's College, Cambridge. He was an undergraduate there from 1931 to 1934, graduating with first-class honours in Mathematics. HP G62-452SA Battery

In 1935, at the young age of 22, he was elected a fellow at King's on the strength of a dissertation in which he proved the central limit theorem,[23] despite the fact that he had failed to find out that it had already been proved in 1922 by Jarl Waldemar Lindeberg.[24]HP G62-454TU Battery

In 1928, German mathematician David Hilbert had called attention to the Entscheidungsproblem (decision problem). In his momentous paper "On Computable Numbers, with an Application to the Entscheidungsproblem" HP G62-456TU Battery

 (submitted on 28 May 1936 and delivered 12 November),[25] Turing reformulated Kurt Gödel's 1931 results on the limits of proof and computation, replacing Gödel's universal arithmetic-based formal language with what became known as Turing machines, HP G62-460TX Battery

formal and simple hypothetical devices. He proved that some such machine would be capable of performing any conceivable mathematical computation if it were representable as an algorithm. HP G62-467TX Battery

He went on to prove that there was no solution to the Entscheidungsproblem by first showing that the halting problem for Turing machines is undecidable: in general, it is not possible to decide algorithmically, whether a given Turing machine will ever halt. HP G62-468TX Battery

While his proof was published shortly after Alonzo Church's equivalent proof in respect of his lambda calculus, Turing was unaware of Church's work at the time that he developed it.[26] Turing's approach is considerably more accessible and intuitive than Church's. HP G62-550EE Battery

It was also novel in its notion of a 'Universal Machine' (now known as a Universal Turing machine), with the idea that such a machine could perform the tasks of any other machine, or in other words, is provably capable of computing anything that is computable. HP G62-a00 Battery

Turing machines are to this day a central object of study in theory of computation. In his memoirs Turing wrote that he was disappointed about the reception of this 1936 paper, which also introduced the notion of definable numbers, and that only two people had reacted – these being Heinrich Scholz and Richard Bevan Braithwaite.[citation needed]HP G62-a00EF Battery

From September 1936 to July 1938 he spent most of his time at the Institute for Advanced Study, Princeton, New Jersey, studying under Alonzo Church. In addition to his purely mathematical work, he studied cryptology and also built three of four stages of an electro-mechanical binary multiplier.[27]HP G62-a01SA Battery

 In June 1938 he obtained his PhD from Princeton University; his dissertation (Systems of Logic Based on Ordinals[28]) introduced the concept of ordinal logic and the notion ofrelative computing, where Turing machines are augmented with so-called oracles, allowing a study of problems that cannot be solved by a Turing machine. HP G62-a03SA Battery

Back in Cambridge, he attended lectures by Ludwig Wittgenstein about the foundations of mathematics.[29] The two argued and disagreed, with Turing defendingformalism and Wittgenstein arguing that mathematics does not discover any absolute truths but rather invents them.[30] He also started to work part-time with the Government Code and Cypher School (GCCS). HP G62-a04EA Battery

Cryptanalysis

During the Second World War, Turing was a leading participant in the breaking of German ciphers at Bletchley Park. The historian and wartime codebreaker Asa Briggs has said: HP G62-a04SA Battery

You needed exceptional talent, you needed genius at Bletchley and Turing's was that genius.[31]

From September 1938, Turing had been working part-time with the Government Code and Cypher School (GCCS), the British code breaking organisation. He concentrated on Cryptanalysis of the Enigma, with Dilly Knox, a senior GCCS codebreaker.[32] HP G62-a10SA Battery

Soon after the July 1939 Warsaw meeting at which the Polish Cipher Bureau had provided the British and French with the details of the wiring of Enigma rotors and their method of decrypting Enigma messages, Turing and Knox started to work on a less fragile approach to the problem.[33] HP G62-a13SA Battery

The Polish method relied on an insecure indicator procedure that the Germans were likely to change, which they did in May 1940. Turing's approach was more general, using crib-based decryption for which he produced the initial functional specification of the bombe. HP G62-a13SE Battery

On 4 September 1939, the day after the UK declared war on Germany, Turing reported to Bletchley Park, the wartime station of GCCS.[34] Specifying the bombe was the first of five major cryptanalytical advances that Turing made during the war. The others were: HP G62-a15EO Battery

deducing the indicator procedure used by the German navy; developing a statistical procedure for making much more efficient use of the bombes dubbed Banburismus; developing a procedure for working out the cam settings of the wheels of the Lorenz SZ 40/42 (Tunny) dubbedTuringery and, towards the end of the war, the development of a portable secure voice scrambler at Hanslope Park that was codenamed Delilah. HP G62-a15SA Battery

By using statistical techniques to optimise the trial of different possibilities in the code breaking process, Turing made an innovative contribution to the subject. He wrote two papers discussing mathematical approaches which were entitled Report on the applications of probability to cryptography[35] HP G62-a16SA Battery

and Paper on statistics of repetitions[36] which were of such value to GCCS and its successor GCHQ, that they were not released to the UK National Archives until April 2012, shortly before the centenary of his birth. A GCHQ mathematician said at the time that the fact that the contents had been restricted for some 70 years demonstrated their importance.[37]HP G62-a17EA Battery

Turing had something of a reputation for eccentricity at Bletchley Park. He was known to his colleagues as 'Prof' and his Treatise on Enigma was known as 'The Prof's Book'.[38] Jack Good, a cryptanalyst who worked with him, is quoted by Ronald Lewin as having said of Turing: HP G62-a17SA Battery

in the first week of June each year he would get a bad attack of hay fever, and he would cycle to the office wearing a service gas mask to keep the pollen off. His bicycle had a fault: the chain would come off at regular intervals. HP G62-a18SA Battery

 Instead of having it mended he would count the number of times the pedals went round and would get off the bicycle in time to adjust the chain by hand. Another of his eccentricities is that he chained his mug to the radiator pipes to prevent it being stolen.[39]HP G62-a19EA Battery

While working at Bletchley, Turing, a talented long-distance runner, occasionally ran the 40 miles (64 km) to London when he was needed for high-level meetings,[40] and he was capable of world-class marathon standards.[41]HP G62-a19SA Battery

In 1945, Turing was awarded the OBE for his wartime services, but his work remained secret for many years.

Within weeks of arriving at Bletchley Park,[34] Turing had specified an electromechanical machine that could help break Enigma more effectively than the Polish bomba kryptologiczna, HP G62-a20SA Battery

from which its name was derived. The bombe, with an enhancement suggested by mathematician Gordon Welchman, became one of the primary tools, and the major automated one, used to attack Enigma-enciphered messages. HP G62-a21EA Battery

Jack Good opined:

Turing's most important contribution, I think, was of part of the design of the bombe, the cryptanalytic machine. He had the idea that you could use, in effect, a theorem in logic which sounds to the untrained ear rather absurd; namely that from a contradiction, you can deduce everything.[42]HP G62-a21SA Battery

The bombe searched for possible correct settings used for an Enigma message (i.e. rotor order, rotor settings and plugboard settings), using a suitable crib: a fragment of probable plaintext. For each possible setting of the rotors (which had of the order of 1019 states, HP G62-a22SA Battery

or 1022 for the four-rotor U-boat variant),[43] the bombe performed a chain of logical deductions based on the crib, implemented electrically. HP G62-a22SE Battery

Most of the possible settings would cause contradictions and be discarded, leaving only a few to be investigated in detail. The first bombe was installed on 18 March 1940.[44] More than two hundred bombes were in operation by the end of the war.[45]HP G62-a23SA Battery

HUT 8 AND NAVAL ENIGMA

Turing decided to tackle the particularly difficult problem of German naval Enigma "because no one else was doing anything about it and I could have it to myself".[47] In December 1939, Turing solved the essential part of the naval indicator system, which was more complex than the indicator systems used by the other services.[47][48]HP G62-a24SA Battery

 That same night he also conceived of the idea of Banburismus, a sequential statistical technique (what Abraham Wald later called sequential analysis) to assist in breaking naval Enigma, "though I was not sure that it would work in practice, HP G62-a25EA Battery

and was not in fact sure until some days had actually broken".[47] For this he invented a measure of weight of evidence that he called the Ban. Banburismus could rule out certain sequences of the Enigma rotors, substantially reducing the time needed to test settings on the bombes. HP G62-a25SA Battery

In 1941, Turing proposed marriage to Hut 8 co-worker Joan Clarke, a fellow mathematician and cryptanalyst, but their engagement was short-lived. After admitting his homosexuality to his fiancée, who was reportedly "unfazed" by the revelation, Turing decided that he could not go through with the marriage.[49]HP G62-a26SA Battery

Turing travelled to the United States in November 1942[50] and worked with U.S. Navy cryptanalysts on Naval Enigma and bombe construction in Washington, visiting their Computing Machine Laboratory at Dayton, Ohio. His reaction to the American Bombe design was far from enthusiastic: HP G62-a27SA Battery

HP G62-a28SA Battery

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