Smallpox, Syphilis and Salvation

by Sheryl Persson

  Oxford University was never to receive the financial rewards that were its due. It was US companies and individuals who eventually enjoyed the astronomical profits generated by penicillin. The ultimate irony was that for 25 years after World War II the British, along with everyone else, had to pay royalties to the United States on the wonder drug that had been discovered, researched and developed in Britain. Ernst Chain had been right.

  When Florey and Heatley arrived in the United States a friend of Florey’s, in what was a million-to-one chance, suggested he visit an obscure agricultural research centre in Peoria in Illinois, the middle of the American wheat belt. The Department of Agriculture’s North Region Research Laboratories had developed a fermentation process that would be suitable for penicillin. The director of the laboratories, Dr May, and the head of the Fermentation Division, Dr Coghill, agreed to take on the task of increasing the yield of penicillin.

  While Florey visited US drug companies, initially without success—although some began their own experiments—Heatley stayed in Peoria and worked at the research laboratory with an American scientist, Dr A.J. Moyer, who 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, Moyer and Heatley were able to push up yields of penicillin from 1–2 units per millilitre to 20 units per millilitre.[44] In the midst of this success Heatley began to notice that his working relationship with Moyer, who seemed decidedly anti-British, had become one-sided with Moyer no longer sharing information.

  In December 1941, Pearl Harbor was bombed by the Japanese, and America entered the war. This event changed everything. Self-interest now meant the United States government considered penicillin of national importance. Its production soon took second place only to the Manhattan Project, the development of the atomic bomb.[45] Funding was no longer an issue. At Peoria yields had improved but not in sufficient quantities to meet military demand and certainly not for civilian needs. What was needed was a new strain of the mould that would be more suited to the deep fermentation processes that had been developed to increase production.

  Military personnel around the world collected handfuls of soil containing moulds that were flown to Peoria and analysed. Local people collected mould. Even the tea lady at the laboratory rummaged through rubbish bins collecting old socks, soggy newspapers and rotting food. One day she brought in a decaying piece of cantaloupe (rockmelon) that she had found in a Peoria market. The mould growing on it produced penicillin 3000 times more effective than Fleming’s original mould.[46] The local mouldy melon was the answer and the tea lady earned the honourable nickname ‘Mouldy Mary’.

  ***

  Florey returned to Oxford in September 1941 but Heatley stayed in Peoria until December and then spent six months working for Merck & Co. Inc. pharmaceutical company in New Jersey. After returning to Oxford in July 1942, Heatley soon learnt why Moyer had become so secretive. Despite an original contract stipulating that any publications should be jointly authored, when Moyer published the results of their collective research he omitted Heatley’s name. In so doing, Moyer was able to apply for patents naming himself as the sole inventor.[47] This was not the last time Heatley would not be acknowledged for his work.

  In 1942 Norman Heatley’s contract with the Dunn School expired and he sought employment elsewhere. The possible loss of one of his most productive researchers came as a total surprise to Howard Florey. It is reported that Florey berated Heatley for wanting to leave, dumbfounded that he would want to do so. For his part, Heatley had no idea that Florey would simply have expected him to stay on. Heatley himself said that when the dust cleared on what had been a mutual misunderstanding he was delighted to remain with Florey. In fact, Norman Heatley stayed at Oxford for the rest of his career, continuing his research on antibiotics and writing or co-authoring 65 scientific papers.

  It was also in 1942, when he was busier than ever, that Florey unexpectedly and for the second time in his life heard from Alexander Fleming. Fleming had visited the Oxford team only once in August 1940 when he became aware of their work on penicillin. He had made very little comment and left as abruptly as he came. This time, when a close friend of Fleming’s was dying of bacterial meningitis and Fleming had tried unsuccessfully for more than a week to cure him with sulfa drugs, the ‘discoverer’ of penicillin, in a panic, on a Sunday morning, telephoned the man who had developed penicillin and pleaded for some.[48]

  Generously but unwisely, Florey travelled to London and gave Fleming powdered penicillin with instructions on dosage and how to inject it. Fleming treated his friend and saved his life. It was revolutionary. Hospital administrators at St Mary’s invited the press to the hospital to announce a modern miracle. Fleming was ready in his white coat to claim his place in history. In August 1942, Alexander Fleming, the man who had returned to studying nasal secretions after putting penicillin aside, found himself, some would say not unwittingly, the centre of international media attention.

  When journalists went to Oxford to get the other side of the story, because there certainly was one, Florey refused to be interviewed. Later he explained that he believed publicity would have had a detrimental effect by creating a huge demand for a drug that was in scarce supply.[49] So the man who was available to the media was the man the media sought. Florey did in fact receive no end of entreaties for penicillin from desperate people. At times Florey wrote replies himself, often getting Margaret Jennings to edit them and soften his somewhat abrupt and seemingly unsympathetic style.

  Fleming happily took the limelight that Florey eschewed. As the number of deaths caused by bacterial infections plummeted, penicillin was being hailed all over the world and Fleming travelled to America where he met Ann Miller, the first person to have been successfully treated with penicillin in the United States. She was cured literally overnight and her temperature chart is now preserved in the Smithsonian Institute in Washington. Fleming had not been involved in her case in any way but when he met her he claimed, ‘this is my most important patient’.[50] It would seem that Fleming was an early master of spin and not averse to self-aggrandisement. Ann Miller died in 1999, 57 years after being treated with penicillin.

  In the United States the government had wasted no time, recruiting more than twenty chemical companies to produce penicillin. Between January and May 1943, only 400 million units of penicillin were made. Then researchers at Pfizer devised a method for growing penicillin in three dimensions, like brewing beer, which exponentially increased the yield.[51] Mass production went into full swing by the end of 1943. There was enough penicillin to meet the demand of Allied casualties when the Allied Forces invaded Normandy on D-day, June 1944, the offensive that turned the tide against the Germans in Europe. By the time the war ended in 1945, only four years after the first mouse experiments, US companies were making 650 billion units of penicillin a month.[52]

  Florey’s part in the penicillin story continued. In 1943, with Hugh Cairns, a professor of surgery at Oxford and a fellow Rhodes scholar from Adelaide, Florey flew to the North African battle zone to test penicillin on wounded soldiers. He wrote to Ethel describing the carnage and the horrendous wounds and infections some soldiers had endured for months without receiving proper treatment, and in some cases no treatment at all.[53] The trials were an unmitigated success. Florey revolutionised the treatment of war wounds. Instead of amputating wounded limbs or leaving wounds open to minimise the risk of infection, as was common practice, wounds were cleaned, sewn up and penicillin injected into the site. As is usual with anything new, field surgeons were furious and vociferously ridiculed the procedure, but not for long.

  It was during the war that penicillin also became the method for curing the venereal disease gonorrhoea, which was rife amongst the troops. Military commanders were astonished that one or two injections of penicillin cured the disease. Thousands of troops who were due to take part in the invasion of Sicily in July 1943 were infect
ed with gonorrhoea and the commanders appealed for penicillin to treat their soldiers so that they could return to their units. Florey and Cairns felt that penicillin should be reserved for battle casualties, but when one of the generals referred the matter to Winston Churchill, Churchill sent back a somewhat ambiguous note saying that the drug should not be wasted but must be used ‘to the best military advantage’.[54] The generals determined that the best military advantage was to use penicillin so that their soldiers could be soldiers.

  The benefits of penicillin were enormous and the world was indebted to Howard Florey but he continued to shun publicity and his vital role was not widely known. This was in keeping with his personality. Florey was humble about his achievements, describing the development of penicillin in an interview in 1967 as a ‘terrible amount of luck’ that ‘involved many others’.[55] He was a quiet man in an assertive way, sure of himself and his direction. His scientific enthusiasm, exceptional skill, his total honesty and lack of pretentiousness inspired those around him. Professor Gwyn McFarlane, who first met Florey in 1938, wrote in her biography of him that Florey’s extraordinary dedication and enthusiasm was very infectious, and the commitment of the Oxford team was evidence of that.

  The relationship between Ernst Chain and Howard Florey, however, became increasingly difficult and their difference of opinion over patenting penicillin sounded the death knell. Chain was eventually vindicated. By not taking out the patent Florey had failed to acquire funds and prestige that would have provided equipment and autonomy on the scale that Chain thought he and Florey should have at Oxford. Whatever Chain’s motives had been, the loss of the patent had a detrimental effect on the team and the university and, in fact, on the entire pharmaceutical industry in Britain.

  AFTER THE WAR

  In 1945, when Florey, Chain, and Fleming equally shared the Nobel Prize for Physiology or Medicine ‘for the discovery of penicillin and its curative effect in various infectious diseases’, the man who had made the trials possible, Norman Heatley, remained in the background. Florey led the work, Chain’s contribution to determining penicillin’s chemical make-up was critical, and Fleming had given them a starting point when he ‘discovered’ penicillin in 1928. But the 1945 Nobel Prize, so the story goes, was very nearly given solely to Alexander Fleming because of the public perception that he alone had discovered the magic penicillin and turned it into a miracle drug.

  Ernst Chain left the Oxford team in 1948 when he was appointed Scientific Director of the International Research Centre for Chemical Microbiology at the Istituto Superiore di Sanità in Rome. In the same year he married Dr Anne Beloff and they had two sons, Benjamin and Daniel, and one daughter, Judith. After 1948 Chain’s research interests continued to be varied and throughout his long career he co-authored many scientific papers. In 1961 Chain returned to England and joined the faculty of Imperial College University of London, where he held various positions including Professor of Biochemistry, professor emeritus and senior research fellow, remaining a fellow until his death on 12 August 1979.[56]

  Ernst Chain’s list of honours is extremely long. He held honorary degrees from innumerable universities and was a member or fellow of many learned societies in several countries. In addition to the Nobel Prize he was awarded, among others, the Paul Ehrlich Centenary Prize in 1954. Ernst Chain received a knighthood in 1969 from the Queen of England, the country in which he and Howard Florey had laboured under the most difficult of conditions to ensure the successful development of penicillin.

  Awards and accolades came to Fleming in rapid succession, including a knighthood in 1944. On 6 June 1954, the 25th anniversary of the discovery of penicillin was celebrated at St Mary’s Hospital Medical School in the presence of Prince Philip, the Duke of Edinburgh. Sir Alexander Fleming presented the duke with a culture plate with a specimen of penicillin mould.[57] Fleming’s death after a heart attack in 1955 was broadcast around the world and he was buried as a national hero in the crypt of St Paul’s Cathedral in London. Although Fleming’s scientific oeuvre may not have reached greatness, his singular contribution, discovering penicillin, changed the practice of medicine and deserves recognition, but not at the expense of those who developed it. Alexander Fleming once said: ‘One sometimes finds what one is not looking for.’[58] In this instance he was probably not referring to fame and publicity.

  Sir Robert Menzies, the Australian prime minister during the first three years of World War II, said of Howard Florey that he had more effect on the welfare of the world than any other Australian. But Florey did not ascribe any altruistic motives to himself. In an interview recorded by the National Library of Australia in 1967 Florey said that there are many misconceptions when it comes to medical research.

  People sometimes think that I and the others worked on penicillin because we were interested in suffering humanity. I don’t think it ever crossed our minds about suffering humanity. This was an interesting scientific exercise, and because it was of some use in medicine was very gratifying, but this was not the reason that we started working on it.[59]***

  Howard Florey’s scientific contributions were not limited to penicillin. Like Louis Pasteur, Robert Koch and Alexandre Yersin before him, his work was eclectic. Florey also studied the role of white cells in the fight against viruses and bacteria. Another branch of his research involved the lining of the stomach and why it is not eroded by acid and bodily secretions. Gus Fraenkel explained that the motivation for this research was personal, beginning when Florey, because he was plagued with indigestion, had examined the contents of his own stomach and found that it contained no acid. Florey’s subsequent published research on mucous secretion in the gut forms a theoretical base for an outstanding and more recent medical breakthrough: the cure for stomach ulcers. In the 1980s another Australian scientist, Professor Barry Marshall, like Florey, literally studied his own gut. Using the Haffkine technique—try it on yourself first—Marshall gave himself stomach ulcers by drinking a Petri dish of bacteria. He wanted to prove to a sceptical world that ulcers were not caused by stress or smoking, but by the bacteria Helicobacter pylori. This gung-ho approach eventually changed stomach ulcer treatment worldwide. But there is a recurring theme: in 1982, when Barry Marshall and pathologist Robin Warren cultured Helicobacter pylori and developed their hypothesis on the bacterial cause of peptic ulcers and gastric cancer, the theory was immediately ridiculed by the members of the medical and scientific establishment. They dismissed totally the idea that any bacteria could live in the acidic stomach.

  Marshall and Warren proved them wrong and in 1984, applying Koch’s postulates, showed that the Helicobacter pylori are the cause of stomach ulcers and gastritis.[60] To kill the bacteria they used different kinds of penicillin . Marshall believes that without Howard Florey’s discovery theirs would not have been possible but also, and paradoxically, the discovery of antibiotics and penicillin may have put a stop to research on Helicobacter pylori.[61] In the first half of the twentieth century scientists like Florey and Fleming were researching bacteria in the stomach but then lost interest because of a plethora of new discoveries such as penicillin and other antibiotics. As Ernst Chain had done, Marshall and Warren resurrected some of the old ideas they found in reports of Helicobacter pylori going back over 100 years. In 2005 Marshall and Warren won a Nobel Prize for their work. In medical science one path certainly leads on to another.

  Because of his prodigious scientific output, by the early 1940s Howard Florey was elected to the Royal Society, the oldest and most famous scientific establishment in the world. For his role as the leader of the team of scientists that developed penicillin and its influence on the outcome of World War II he was honoured and decorated around the world. In 1960, twenty years after being elected to the Royal Society, Florey became its president, the first pathologist and the first Australian to hold this prestigious position. He became affectionately known as ‘the Bushranger President’.[62]

  Ethel Florey’s contribution was recogni
sed in her home country in 1950 when Adelaide University honoured her with an MD, Doctor of Medicine. The separation from her children had given Ethel the opportunity to throw herself into the clinical work on penicillin throughout the war and afterwards. Once the trials had begun in earnest she was involved in the selection of patients, control of treatment, organisation of tests and record keeping and was on call 24 hours a day, seven days a week. Ethel and Howard published the results of 187 cases of septic infection treated with penicillin in an article in The Lancet on 27 March 1943. This was the first of the series of clinical trials that Ethel conducted.[63] However, she was never given a bona fide hospital appointment and officials came to regard her simply as Howard’s assistant.

  Ethel Florey published the results of her clinical work in two volumes, the first in 1952 and the second in 1957. She and her husband left Oxford for three years in 1957 while they built a house in Old Marston, a picture-postcard village a few miles north of Oxford. Ethel’s health continued to become more precarious. She had recurrent respiratory illnesses and developed hypertension and heart problems and an operation to relieve her deafness was unsuccessful. Ethel’s youthful determination remained with her and after suffering a myocardial infarct she travelled alone to America in 1965 to lecture, and then to Australia to visit friends and relatives.

  That year was a busy one for Howard Florey as well. He was elevated to the peerage by the Queen of England and was made Baron Lord Florey of Adelaide and Marston. He also accepted the inaugural Chancellorship of the Australian National University, which he helped to establish. In the midst of all this, Ethel’s health was rapidly deteriorating. In the spring of 1966 she went to America for her son’s wedding and not long after her return died on 10 October at Marston. A long marriage that had been far from happy came to an end.