Everyone knows that Alexander Fleming discovered penicillin by accident; that was in 1928. But penicillin, though a potent antibiotic, was difficult to purify, and yields were low and unpredictable. It seemed destined to remain merely of academic interest. By the outbreak of the Second World War in 1939, little progress had been made. But by D-Day on June 6, 1944, the allies had in stock enough penicillin to treat all those who were wounded and needed it.
It was largely due to the technical ingenuity of one man that enough penicillin was produced for the first hospital tests. That man was Norman Heatley, who had to surmount some rather unusual difficulties to achieve his goal.
Heatley was born in the small town of Woodbridge in the county of Suffolk, England, where his father was a veterinarian. Heatley's interest in science was triggered by a speaker who visited his local school, and it was reinforced by having good science teachers at the boarding schools his parents sent him to, first at Folkestone and then at Tonbridge. From the latter he went to Cambridge where he graduated in 1933; he then stayed on to do a Ph.D. in biochemistry.
His first ambition on leaving university was to set up his own commercial analytical service, but the project was dropped when he was offered a temporary job at Oxford University. There his practical skills were to prove invaluable in helping to turn penicillin from an academic curiosity into the lifesaving drug that transformed medical treatment worldwide.
Today, Heatley, now 84, lives in the same house he and his wife, Mercy, bought in 1948 and in which they raised their family.It is a modest country cottage in the picture-postcard village of Old Marston, a few miles north of Oxford. And there Science Watch chemistry correspondent John Emsley encountered the man with a remarkable tale to tell.
On Christmas Eve 1940 Norman Heatley and his fellow workers in the Sir William Dunn School of Pathology at Oxford University spent the day washing, sterilizing, and filling dozens of the new fermentation vessels which he had designed for producing penicillin. On Christmas Day Heatley returned to the lab and seeded them with the spores of the fungus Penicillium notatum and stacked them for their ten-day period of incubation, at the end of which time he hoped the liquid on which the fungus was growing would contain enough penicillin to begin tests on humans.
Seven months previously, on Saturday, May 25, 1940, Heatley had played a key role in the first experiments which proved the remarkable antibiotic power of penicillin on animals. He had watched hour-by-hour over eight mice, each of which had been injected that morning with 110 million streptococci, a virulent strain that would kill within a day. Four of the mice were injected an hour later with doses of penicillin solution; the other four remained as controls.
Heatley watched and waited. By late afternoon the four controls were already sick, and they began to die soon after midnight. By 3:30 a.m. all were dead. The four treated with penicillin were fine. Heatley cycled back to his rooms through wartime, blacked-out Oxford to snatch a few hours sleep before returning to the labthere to tell his supervisor, Professor Howard Florey, head of the Dunn School, the good news."It looks quite promising," was Florey's assessment of the result. In fact it was little short of a miracle.
However, Florey knew that a human is about 3,000 times heavier than a mouse and would need a correspondingly large dose of penicillin. The makeshift pie dishes, biscuit tins, and hospital bedpans that Heatley had been using as fermentation vessels were no longer adequate. It was essential to scale up production, but outside events were to intervene to thwart their plans. The yearlong Battle of Britain was then at its height, with Luftwaffe air raids on towns and cities night after night. Pharmaceutical companies, which had the equipment to culture microorganisms in the amount that Florey required, were unwilling to divert people and resources from the war effort into producing what was still an untested drug.
Florey's only recourse was to try and produce penicillin on a pilot plant scale at the Dunn School. He looked to Heatley, the man who had been responsible for cultivating the penicillin produced so far. Florey was thus driven to adopt what seemed an almost impossible tasknamely, to try and make enough of the drug in the Dunn School itself to treat a few human cases, and as quickly as possible. This mass-production request was passed to Heatley, who was ably assisted by George Glister and the three or four "Penicillin Girls," who, with little formal training, quickly developed into a willing and efficient team for setting up the cultures and harvesting the penicillin-containing culture fluid. Heatley suggested a useful extraction and purification process that was also used by most industrial producers of the drug for several years. The process was based on the factsknown since 1932that if an acified solution were shaken with ether, the penicillin passed into the ether but did not do so at neutral pH. Heatley's ingenious contribution (which he modestly describes as "laughably simple," though he admits it cost him hard mental effort) was to shake the ether extract with water held at neutral pH with buffer or alkali, which brought the penicillin back into a clean watery phase.
After the successful mouse-protection experiments of early summer 1940, a key requirement was a supply of uniform culture vessels instead of the trays, tins, bottles and such that had been used until then. A rectangular glass vessel was designed. It was the size of a large book, with a spout at one corner, and was ideally shaped for stacking in large numbers for sterilization in the department's small autoclaves. The glass vessels were designed to hold a liter of culture medium at a depth of 1.7 cm, the optimum for fungal growth and penicillin yield. Inquiries at the Pyrex glass company frustrated their plans. The firm was willing to make the glass culture vessels, but there would be an up-front charge of 500 pounds for a special mold (equivalent to about 30,000 pounds or $45,000 at today's prices) and a waiting time of six months.
The resulting gloom and despair were partly abolished when Heatley wondered whether a ceramic vessel might be satisfactory. "I recalled as a boy reading a Royal Institution Christmas Lecture on ceramics, and I particularly admired the ingenious slip-casting process. Could cheap porcelain vessels, similar in shape to the glass vessels, be made by this process? And would the fungus grow in them and produce penicillin? The answer was yes."
The vessels were 28 cm long, 23 cm wide and 6 cm deep, and Heatley suggested that if they were glazed only on the inside they would remain rough on the outside, making them easy to handle. (Heatley still keeps one to show to interested visitors.) Florey decided to try them and wrote to a Dr. J.P. Stock of Stoke-on-Trent, sending him drawings of Heatley's vessels and seeking his help. Stoke-on-Trent is one of five towns collectively known as The Potteries and located in the English Midlandsa place where where fine tableware had been made for hundreds of years. Stock contacted the firm of James MacIntyre and Co., who said they were willing to make the vessels.
According to Heatley things now began to move rapidly. "Stock passed the rough drawings to the firm and telegraphed Florey. I rang them the same day and arranged to visit the following day." Heatley caught the train from Oxford but his 100-mile journey was to take a whole day because of an air raid on Birmingham, through which they had to pass. However, on his arrival at James MacIntyre's he had some good news: "I was amazed to find that they had already made three slightly different models." Heatley chose one, and with a few minor adjustments it was ready for firing and glazing, a process which took about three weeks.
In late November 1940 three trial vessels arrived at the Dunn School and proved completely satisfactory. Florey placed an order for several hundred, and work on them began at once. On December 23 Heatley borrowed a van and brought back the first batch of 174 to Oxford, and on Christmas Day 1940 the Dunn School began to produce penicillin on a scale which could permit tests on humans.
Within a month Heatley had 80 liters of crude penicillin solution, with around 1-2 units of penicillin per milliliter (ml) amounting to around 100,000 units in alla unit being defined in terms of potency measured on a special assay culture plate invented by Heatley. Later it was shown that a unit was equivalent to 0.6 micrograms of pure penicillin. (Development and commercial production were later to increase the yield of penicillin to 40,000 units per ml.)
Florey now thought they had enough penicillin to try it on a human patient. In the Radcliffe Infirmary in Oxford lay a 43-year-old policeman, Albert Alexander, dying of staphylococcal and streptococcal infection contracted when he had scratched his face on a rose bush a few months earlier. Despite the efforts of doctors, his head was covered with suppurated abscesses, one of which had necessitated removal of an eye. Nothing had helped, not even sulphonamides, which are not effective when a patient is saturated with pus. On February 12 he was given an infusion of penicillin and immediately started to improve. More penicillin followed, and more improvement.On February 19 he was well on the way to recovery, but despite recycling penicillin recovered from his urine, the supply was exhausted and the bacteria began to regain their hold. He died on March 15.
The next patient to receive penicillin was Arthur Jones, a lad of 15 who had required a hip operation to insert a pin but whose wound had become septic and who again had not responded to sulphonamides. His temperature had been over 100 degrees F for two weeks. He was given penicillin, and within two days his temperature was normal. Four weeks later he was fit enough to have another operation to remove the pin that had caused the infection.
Successive batches of Heatley's penicillin treated more patients with success. The results of these cases were described in a landmark paper modestly entitled, "Further observations on penicillin," which was published in The Lancet in August of 1941.
All this time Heatley struggled to improve the yield of penicillin. With each batch he set aside one or two pairs of his vessels and varied the culture medium or the conditions, hoping to increase the yield of the antibioticbut without success. But there was no doubt that the Dunn School had proved the efficacy of the new drug. What was now needed was to speed up production. The Rockefeller Foundation, which had been supporting Florey, urged him to visit the United States and seek help from firms there. In July 1941, Florey and Heatley flew to neutral Portugal and there caught the famous Pan-Am Clipper seaplane to New York. A round of meetings followed.
It was at the Department of Agriculture's North Region Research Laboratories at Peoria, Illinois, that their pleas fell on fertile ground. Director of the labs, Dr. May, and the Head of the Fermentation Division, Dr. Coghill, agreed to immediate research aimed at increasing the yield of penicillin above the miniscule 1-2 units per ml obtained at Oxford. Heatley stayed on there, while Florey began a series of visits to U.S. drug companies, again without apparent success, although some now began their own experiments.
In Peoria, Heatley was assigned to work with Dr. A.J. Moyer, who hated all things British. However, the gentle-mannered and quietly spoken Heatley appeared to be an exception and they worked well together. 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, 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, 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, despite an original contract which stipulated that any publications should be jointly authored. Fifty years on, Heatley confesses 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. 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.
Meanwhile, Heatley had other things on his mindhis future employment. Unbelievably he was planning to leave Oxford: "Thinking that my contract with the Dunn School had come to an end, I accepted a job offer elsewhere." Florey was taken by surprise at the possible loss of one of his most productive researchers, and berated Heatley for wanting to leave. "When the dust of this mutual misunderstanding had cleared I was delighted to stay on with Florey," says Heatley. In the end he stayed on for the rest of his career, researching antibiotics and writing or coauthoring 65 scientific papers.
Penicillin's success brought Florey great acclaim and several so-called Honours. He was knighted in 1944, became Baron Florey in 1965, and received the Order of Merit, Britain's highest accolade for creativity. With Ernst Chain, who also worked at the Dunn School, and Alexander Fleming, he shared the 1945 Nobel Prize for Medicine or Physiology. Fleming and Chain were also to be rewarded with knighthoods by a grateful British Government.
Heatley, too, was eventually rewarded and received an Honour, an OBE, Order of the British Empire, when he retired 35 years later in 1978. Oxford University was never to receive the financial rewards that might have been its due. Penicillin generated astronomical profits around the world in the next 20 years, and all these flowed to U.S. companies and individuals. Florey had been persuaded by Sir Henry Dale, Head of the Medical Research Council, that it was unethical to patent a medical discovery, so he didn't. The result of this foolish advice was that for the next 25 years the British also had to pay royalties on the wonder drug that had been discovered, researched, and developed in Britain.
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