A generous Puritan

It is so easy to forget that only 60 years ago they didn't exist. A scratch from a rose bush could be fatal - venereal disease could mean death or madness - quite often both.

Staphylococcal infection was extremely serious. Prior to the Second World War every hospital had its Septic Ward where patients lay with chronic discharging diseases. The only known treatment at the time was bandaging and bed rest.

On average, only 50 per cent of those patients who went into a septic ward came out alive. This was the accepted situation until the arrival of antibiotics around 1944.

So, how do we come to have penicillin today? If you were like me, you were probably shown a picture at school of a man in a white lab coat peering down a microscope and were told that he was Alexander Fleming busy discovering penicillin, and you probably thought no more about it.

Like so many things in history, the story has been simplified to the point of almost total distortion. In 1928, Fleming observed antibiotic activity in a very raw state, wrote up a paper about it taking the line that it was a curious scientific observation'.

He did not predict any medical application for it, let alone do any further research on the subject.

However, his paper about what he had observed was published in The British Journal of Experimental Pathology a year later, and it was read by some key people.

There were a number of unsung heroes and heroines who contributed to the development of penicillin. There were, of course, the vital links - Fleming, Florey, Chain and Heatley, but there was also an enthusiastic science teacher on the East Coast, an observant research assistant, D M Pryce, and the penicillin girls who worked tirelessly in the Dunn School of Pathology during the war, to name but a few.

Norman Heatley was born in Suffolk in 1911. He was the only child of a veterinarian father and an invalid mother.

Famous for his self-sufficiency, one cannot help wondering if this was inadvertently nurtured by his mother, who worried so much about catching anything that if her child showed symptoms of an infectious illness he would be banished to sleep in the summerhouse.

After an unfortunate year at a prep school near Ipswich, which Norman described as the nearest thing to Lord of the Flies', he was sent to Westbourne House, a boarding school on the coast at Folkestone. Here Norman was to experience two things that were to affect the rest of his life.

First of all, he was to make a lifelong friend, Christopher Morcom. Norman was taken for days out and spent many holidays with the Morcoms (for some reason his parents never visited him at school) and came to greatly admire Mrs Morcom - a lady unusually well-educated for the 1930s - trained as a sculptor and also knowledgeable about science. Norman's wife was to say that she was grateful for the example Mrs Morcom had set, as this liberated her from the conventional image of a domestic wife and mother.

Secondly, the preparatory school had an inspirational retired science teacher who still came in once a week to give practical science demonstrations. The day Mr Ullyatt came in to teach was a red-letter day for the boys - and set Norman on track for what was to be not only a great career for himself, but one which was to benefit the whole of mankind.

Norman went up to St John's, Cambridge, in 1929 to read Natural Sciences and stayed on to work on his doctoral thesis, The Application of Microchemical Methods in Biological Problems while at the same time working for the Nobel prizewinner, Frederick Gowland Hopkin, in the Cambridge William Dunn School.

His grasp of his field impressed his peers and also his senior colleague, (Sir) Ernst Chain. Indeed, it was Chain who, after joining Professor Howard Florey's team in the Oxford Dunn School of Pathology, recommended that Norman Heatley be invited for an interview.

That interview led to a three-year appointment to research cancer tumours. He was to stay in Oxford for the rest of his life, and, as the saying goes, the rest is history. But, it is an unsung piece of history, generally known only to family, close friends or informed scientists and medics.

Norman Heatley was to put down deep roots in Oxford: family and home life were tremendously important to him and went hand and hand with his research.

He met Mercy, his wife-to-be, at a dance at Somerville College. It might have been just another date but for the fact that Mercy developed a severe toothache soon after the dance. By the time Norman asked her for a second date she had to refuse due to the pain she was in. Norman turned up on her doorstep with oil of cloves to relieve the pain and it was then she began to realise he was "someone special".

Mercy qualified as a doctor and went on to specialise in psychiatry. She and Norman married in 1944 and had five children (four surviving today).

After the first was delivered in hospital, the subsequent four were born at home with Norman assisting the midwife and taking this role in his stride, a forerunner of "modern man".

On the occasion of the first home birth Mercy exhausted the supply from the gas and air machine they had been loaned. Norman rushed off to the GP's house for another one. He got it home, only to find it was brand-new and still in pieces. He kept calm, and set about assembling the equipment, totally successfully, of course.

Various attempts were made to purify penicillin over the years. Harold Raistrick at the London School of Hygiene and Tropical Medicine tried with a small sample obtained from Fleming. He got as far as being able to dissolve penicillin in ether but, as penicillin in ether was useless as a medicine, he saw no point in going on.

Back in Oxford, Florey wanted Chain and Heatley to work on lysozyme, a component of tears that has a natural antibacterial effect. This led to looking at Penicillium notatum, which was at the time also thought to be an enzyme.

Lysozyme proved to be an enzyme, important in itself, but penicillin turned out to be something unimagined. The age-old, wartime story of lack of funds meant that all this research moved very slowly and Heatley's three-year grant was running out. He was awarded a Rockefeller travelling grant and planned to leave England to study with the famous Danish biochemist, Dr Kaj Ulrik Linderstrom-Lang.

His passage was booked for September 12, 1939. On September 3, Britain declared war on Germany and, not surprisingly, Heatley stayed in Oxford.

Work on penicillin now became urgent and the outbreak of the Second World War meant a standstill on equipment. Florey persuaded the Rockefeller Foundation to let the travel grant become a salary to enable Heatley to stay on at the Dunn School. His ability to improvise and his spirit of "never give up" was a trait he had in common with some of our most famous scientists - Louis Pasteur, for example, made his own apparatus.

Heatley built a counter-current machine (a device which would automatically extract penicillin) from an oak bookcase discarded by the Bodleian Library, glass tubing mostly fashioned by him, an old doorbell to signal when a bottle was empty or full, coloured warning lights, nozzles, copper cooling coils and multiple junctions.

In the 1980s, because nothing was left of the original apparatus, the Science Museum asked Heatley to build a replica which he found much more expensive to assemble than the original.

"Rubbish dumps aren't what they were in the 1940s," he explained.

Money for research had always been tight but the war situation was an even worse scenario. The team needed vessels to hold the "broth" which contained the raw penicillin.

Heatley went round Oxford grocers begging discarded biscuit tins. One good soul sent him to Huntley and Palmers in Reading, where he managed to obtain one hundred tins, unfortunately round and not square, which would have made better use of storage space, but at the time very welcome.

Other containers were pressed into service. Lidded bedpans had been ideal but were now no longer made - the new style wasn't suitable. While dog baths and baking dishes were being added to the list of strange containers, France fell to the Germans in June 1940 and the possibility of invasion seemed imminent. What would happen to their research?

Heatley suggested rubbing spores into their clothing. Thus, if they had to flee, or were arrested, they could still carry their work with them. In July the invasion of Britain seems so imminent that a group from Yale University offered homes to children from Oxford. One hundred and twenty went, including Professor Florey's 10 and 5 year old girl and boy. The ship carrying the children survived a submarine attack and arrived in New Haven. Dr John Fulton, who had known Florey from their days as Rhodes Scholar together in Oxford, saw the children's name on a list and cabled his old colleague: "OXFORD SAILING JUST RECEIVED. MAY WE CLAIM CHARLES AND PAQUITA FOR DURATION?" The response was "VERY MANY THANKS EXTREMELY KIND OF YOU." With his children's safety off his mind Florey turned his attention back to penicillin and came to the conclusion that with their very limited resources the Dunn School could not produce penicillin in anything like the quantity required for proper trials. Industrial help was needed. The Wellcome Foundation was approached but their resources were already stretched to capacity meeting the demand for proven drugs such as vaccines and antitoxins.

A leap forward was made in the August when a way to separate penicillin from its favourite ether solution was discovered. This process came to be called chromatography, details of which were published in the 24 August edition of The Lancet and Professor Florey desperately hoped this would attract the attention of other drug companies, but the timing was poor in that the 25th August saw the start of the London Blitz - everyone was too busy fire fighting and surviving the day to think about medium-term research, however important.

At this point the amount of penicillin being produced was so minute it could be tested only on mice. The quantity of a drug required to test a human is 3,000 times that of a mouse and this is talking about one dose only! Thus, eight very famous, thought nameless, white mice took their place in history, in the second half of 1940, proving that penicillin could cure them of virulent streptococci infections.

Heatley continued agonizing about where to find enough vessels in which to grow the 500 litres of penicillin solution they wanted to produce per week in order to do tests on humans. The biscuit tins were rusting despite precautions. He approached Pyrex who could have made suitable vessels but required £500 upfront to make the mould. This sum was way beyond the Dunn School's budget so another answer had to be found. Heatley came up with the idea of ceramic vessels and sketched some designs. The next thing was a visit to Stoke-on-Trent in the Potteries where it seemed the firm James Macintyre and Company might be willing to make up items according to his design. To cut a long story short, seven hundred were made by this firm and on 22 December 1940 Heatley drove to Stoke in a borrowed Ford van to collect the first consignment. He stayed the night, oversaw the loading of 174 of the new culture vessels, padded in straw for safety, and drove back to Oxford through a snowstorm. Roads signs had been taken down to "confuse the enemy" in the event of an invasion - quite a few Britons were confused as well, including Norman that particular night! Christmas Eve saw the unloading, assembling, sterilizing and setting up of the new vessels. On Christmas Day Heatley sowed 76 of the vessels with a spray gun. What a year! For the past six months Heatley had done no research, he had simply concentrated on the logistics of production.

It soon became evident that more help was needed to run the plant. Over the first half of 1941 six girls were recruited to operate the system- the first time female technicians had been employed at the Dunn School of Pathology. Some were as young as 16 and 17 when they started, all local girls to be remembered with pride: Ruth Callow (now Parker); Claire Inayat; Megan Lancaster (now Nurser); Betty Cooke; Peggy Gardner and Patricia McKegney.

Soon small amounts of penicillin were being produced. No one had a clue what dosage would be appropriate, what might be too much, what side effects there might be, if any. The stage had been reached when real human beings had to be treated. One of the earliest names to be associated with penicillin treatment was Albert Alexander, a 43 year old police constable. History has traditionally recorded that Alexander scratched himself gardening but recently police records have shown that he had been on secondment to Southampton, injured in a bombing raid and sent back to be nursed in Abingdon Hospital. Whatever the cause, or combination of causes, infection set in, and by the time he was transferred to the John Radcliffe, he was, as Heatley's diary records, "oozing pus everywhere". He responded dramatically to treatment - the only problem was the small quantity of penicillin available. The shortage was so acute that Alexander's urine was collected after every dose and bicycled back to the Dunn School so that any unused penicillin might be extracted and re-administered. He appeared to recover and medication ceased, not least because what little penicillin was left was now urgently needed to treat a 15 year old youth who had developed septicaemia following a hip operation. Young Arthur Jones also responded dramatically to treatment, but in the meantime Alexander suddenly started to deteriorate. There was no more penicillin to give him and all the team could do was stand by helplessly and watch him die. No one knew what might be the correct dose or the importance of finishing a course of antibiotics. By the time four more people were treated (a boy and a baby with complete success) the team had used a total of 4 million units - the amount given in a 24 hour period to one person today.

It was becoming obvious that the only chance of enlisting commercial help was to approach American drug companies. After endless letters and meetings with government officials, it was finally agreed, in June 1941, that Professor Florey and Norman Heatley would fly to New York on what had become a mission. Florey went because he was the Head of the Department and he chose Heatley as the vital link, the facilitator. The flight was all very secretive. A Dutch plane took them to Lisbon from where they flew with PanAm arriving at La Guardia Field, New York. Meetings were set up with medical officials and various companies with Florey's old Rhodes Scholar chum, Dr John Fulton helping as much as possible. In the end it was Merck and Company who led the challenge to develop penicillin. Florey returned to Britain but left Heatley behind as the one person who could show the Merck team the practicalities of setting up the system. The first person in the USA to be treated with penicillin was 33 year old Anne Miller, a woman dying of a streptococcus infection following a miscarriage - an all-too-common complication at the time. Her doctor, John Bumstead, had all but given up on her but he had heard that a new drug was being developed and he knew Dr Fulton. He begged for a small quantity of the miracle cure and it was administered. Dr Bumstead was so delighted with his patient's response that he wanted to decrease her dose quite soon, but Heatley remembered Constable Alexander and thought not. However, all this was not without a little daily ritual. Bumstead would ask Heatley's advice; Heatley would reply that he was not medically qualified and that it would be unethical for him to suggest anything. Bumstead would then ask what Heatley thought Professor Florey would advise and Heatley would say "Carry on!" Anne Miller made a full recovery. She died in 1999 at the age of ninety.

The attack on Pearl Harbour in December 1941 galvanized the Americans' attention and the development of penicillin became an urgent medical necessity. Heatley stayed on assisting Merck until he had helped them all he could. Finally, on 2 July 1942 he sailed for England and home - Oxford. Back to austerity; back to making equipment for the laboratory from sealing wax and bits of string and begging for petrol coupons. However, one thing did make it worth coming back and that, of course, was that he was destined to meet a bright young medical student, Mercy Bing, who would become Mrs Heatley.

Mercy says that, as a father, Norman made rabbit hutches second to none. He was always improvising games for the children.To this day a polished plank is secured inside the front of their family home in Old Marston. This plank was laid against the stairs to enable the children to enjoy sliding down on wet days. Another invention was an adapted pram (wheels removed) hoisted up on the first landing to enable smaller children to have "sugar boat" swings in their own house. One can only imagine how popular playing at their house must have been with little school friends. Norman had a very pleasant voice and enjoyed reading aloud to his children at bedtime. One of his favourite books was "The Midnight Folk" by John Masefield and he was also very fond of poetry.

The mind that was to work away on the problem of extracting penicillin and making it into a useable form was also hard at work fixing things at home, making things to entertain his children, solving problems and rescuing situations. He had the foresight to buy the picturesque, medieval but incurably damp cottage next to his house when it came on the market. This he did up, making it into two flats which were then rented to a series of D.Phil students and their families. More than once tenants decided to marry during their time there but no father was available to give away the bride. Naturally Norman stood in. He turned his hand to making wedding punch and converting the fruit left over into delicious marmalade. At one point in his life he claimed to have made a set of bookshelves every summer holiday since becoming a landlord. A leaking water bed was a challenge for Norman. He had never seen one before, but he knew his physics and improvised with a hose to rescue the situation before too much damage was done.

He kept cats, a dog and chickens and was a skilled and enthusiastic gardener. He was particularly interested in the older varieties of English apples such as Lane's Prince Albert. He once had four varieties grafted on to one tree. He grew delicacies such as Jerusalem artichokes and asparagus. He loved flowers and would give away bunches to colleagues and gave one regularly to Lincoln College chapel where he was, by now, the Nuffield (Penicillin) Research Fellow.

At one time Raymond Blanc, who was, even then very well known, bought the house next door. Norman announced his intension of making an apple crumble and taking it round to welcome him as a new neighbour. Mercy, knowing that Raymond was already an established and successful chef, felt embarrassed and tried to dissuade him. Many years later when dining in Raymond Blanc's restaurant in Walton Street she reintroduced herself to Raymond and asked if he had ever received the apple crumble. "Yes," said Raymond Blanc, "I was delighted. I had thought of English people as cold and unfriendly. Your husband changed my mind."

Later in life Norman acquired a dormobile and when invited to visit and stay the night would reply that he would be delighted to do so, but that he would sleep in the dormobile and come in only for a bath.

His wife, Mercy, describes Norman as a "generous Puritan". Generous to others he would struggle to spend any money on himself. The older his clothes were the more he preferred them. He rode one particular bicycle for some 15 years. Eventually he traded it in during what happened to be a Road Safety Week. The shop placed Norman's bicycle in the middle of its window with a notice which read: "until yesterday this bicycle was actually being ridden". Faulty handlebars, saddle and pedals were flagged up. In the area of Oxford where Norman and Mercy lived they became known as the kindest of neighbours. As the years went by, and the residents who hadn't moved on became older, Norman became well known for rescuing people including E.R. Dodds, sometime Regius Professor of Greek, who did not so much lock himself out, as lock himself in! Norman naturally added lock picking to his list of skills.

In the German language there is a perfect expression for a person like Norman. Er ist ein Mensch - he is a soul. Norman Heatley was a man who certainly grew his soul. The world was richer because of him. He was, truly, a spiritual son of Oxford.

The Sir William Dunn School of Pathology and Lincoln College are seeking funds to establish a postdoctoral award to celebrate Dr Heatley's contribution to science in the 20th century. For further information contact Susan Harrison on 01865 279838 or email susan.harrison@lincoln.ox.ac.uk.