Norman Heatley

Last survivor of the team that developed penicillin

Norman George Heatley, experimental pathologist: born Woodbridge, Suffolk 10 January 1911; scientific staff, Sir William Dunn School of Pathology, Oxford University 1936-78; Nuffield Research Fellow, Lincoln College, Oxford 1948-78, Honorary Fellow 1978-2004; OBE 1978; married 1944 Mercy Bing (two sons, two daughters, and one son deceased); died Oxford 5 January 2004.

Norman Heatley was the last surviving scientific member of the team that developed penicillin as the "miracle drug" in the early 1940s. He has often been described as the unsung hero of the penicillin story. Those who knew him will readily understand why. Heatley was the most delightful "old-fashioned gentleman". He was modest to a fault, courteous, kind, considerate and constantly trying to find ways to help colleagues and friends. He was a team player, rather than a leader of men.

Many myths surround the origins of penicillin: from the Oxford perspective the most important and difficult of these, particularly since it is what most schoolchildren are taught, is that Alexander Fleming not only "discovered" penicillin (which he did, essentially by accident, in 1928) but that he gave the antibiotic ready to treat the grateful, waiting world.

The truth is that Fleming and his colleagues working at St Mary's Hospital, Paddington, in London actually found that the culture extract containing penicillin was unstable and the antibiotic was impossible to isolate in a pure state and so they effectively gave up research on it. Only when the pathologist Howard Florey and the biochemist Ernst Chain at the Sir William Dunn School of Pathology in Oxford decided to work on antibacterial substances in 1939 was serious research on penicillin resumed.

When its importance became apparent in 1940, Fleming contacted Florey and visited Oxford to learn more about the "breakthrough". (At this time Chain is reputed to have said that he thought Fleming was already dead.) But St Mary's Hospital - this was pre-NHS of course - realised the enormous publicity value of their link with penicillin and the Dean, Lord Moran, along with the hospital's patron Lord Beaverbrook were prominent in encouraging the press to publicise and exaggerate the contribution of Fleming and to play down the importance of the Oxford work. Florey himself must bear some responsibility for the distorted stories put out by the media because he consistently refused to speak to them and forbade his colleagues to do so.

In a Florey Centenary Lecture given in 1998, Professor Sir Henry Harris (Florey's successor as Professor of Pathology at Oxford) succinctly summed up by saying: "without Fleming, no Florey or Chain, without Chain no Florey, without Florey no Heatley, without Heatley no penicillin".

It is bordering on the bizarre that, while Fleming apparently received 25 honorary degrees, 26 medals, 18 prizes, 13 decorations, the freedom of 15 cities and honorary membership of 89 scientific societies and academies, Heatley received one honorary degree (from Oxford in 1990 - an Honorary Doctorate in Medicine, the first given to a non-medic in the university's 800-year history and, in Heatley's view, "an enormous privilege, since I am not medically qualified") and was appointed OBE in 1978. We might speculate that he missed out on the Nobel Prize given to Fleming, Florey and Chain in 1945 only because the rules of the Nobel committee restrict the number elected for an award to three. When it was suggested to him that he should have received a knighthood, Heatley's characteristic response was to shrug his shoulders and say: "Oh well . . ."

What he did get in large measure was the enormous satisfaction of knowing that he was a key part of the team that gave the world its first practical antibiotic; one that saved the limbs and lives of thousands of Allied troops in the Second World War, and literally millions of patients all round the world since then. Few individuals have combined the talent, opportunity and good fortune to make such an impact on the world.

As a result of the penicillin work Lord Nuffield endowed three Research Fellowships at Lincoln College, Oxford. Heatley was elected to one of these (Edward Abraham and Gordon Sanders, two other members of the penicillin team, were elected to the others). His close involvement with Lincoln College continued for the rest of his life and gave much pleasure to both parties.

Norman George Heatley was born in 1911 at Woodbridge in Suffolk. He was blessed with a charismatic science teacher at prep school in Folkestone who instilled a lifelong interest in practical science. He moved on to Tonbridge School and then to St John's College, Cambridge, where, after graduating in Natural Sciences in 1933, he stayed on to research for a PhD in Biochemistry. Soon afterwards he was invited to come to Oxford to work with Chain and Florey on research into antibacterial substances.

Ernst Chain had found Fleming's 1929 article about penicillin and urged Florey to investigate its properties further. With Chain, Heatley's role was to look at the growth, isolation and chemistry of the substances under study while Florey studied their biological properties. It soon emerged that penicillin was far more effective in fighting bacteria than the other anti-bacterial candidates but there was no simple way to measure its activity or to extract and purify it from the culture fluid.

Heatley's genius for invention solved both these problems. He devised a new assay method that measured the activity of penicillin precisely, in what became known as "Oxford units". He also found appropriate conditions under which penicillin was stable and applied a multi-stage technique to isolate it from the culture fluid and concentrate it. The procedure was automated, using the now famous Heath Robinson set-up of bath, milk-churns, petrol cans and biscuit-tin lids, etc, and yards of glass and rubber tubing. Despite its improvisation the basic principles of the method are still used today to produce penicillin.

He also played a key role with Florey in the first experiment that demonstrated penicillin's remarkable power in animals. At 11am on Saturday 25 May 1940, eight mice were injected with a lethal dose of virulent streptococci bacteria. One hour later four were given an injection of penicillin (two were given repeated injections). Heatley stayed in the laboratory until 3.30 the following morning, by which time all the untreated mice were dead and all the treated mice lively. The experiment was repeated the next day with the same results. This was no statistical fluke.

It was now clear that a trial of treatment in human patients was urgently needed. But a human is 3,000 times larger than a mouse and the amount needed to treat humans would require large-scale production, which in wartime no commercial firm in Britain was able to undertake.

The Dunn School was turned into a production factory utilising several hundred Heatley-designed ceramic "bed-pans" for the growth of the penicillin cultures. These were looked after by six specially recruited technicians, known as the "penicillin girls". After extraction and purification, the dry powder produced turned out to be less than 1 per cent pure but was nevertheless deemed suitable for a clinical trial.

The first patient to be treated was Albert Alexander, a virtually moribund policeman who received his first injection of penicillin at the Radcliffe Infirmary, Oxford, on 12 February 1941. After five days he had improved dramatically but unfortunately the penicillin had all been used and he slowly regressed and died on 15 March.

Other patients in the trial were "cured" and overall it was clear that penicillin really was a "miracle drug". These results were published in The Lancet in August 1941. By now it was obvious that penicillin could be an effective treatment for infection and thereby make a very important contribution to the war effort, and to the morale of injured troops. But increasing the yield of the batches of antibiotic proved impossible without industrial-scale production.

Accordingly, in late June 1941, Florey and Heatley flew to New York, to seek help from firms less restricted by wartime production than those in the UK. While Florey sought help from the "top brass" in US research circles and the pharmaceutical industry, and indeed persuaded them to collaborate, Heatley worked with government scientists at the Northern Regional Research Laboratory at Peoria, Illinois.

Improvements in the growth medium (corn steep liquor) and the use of a different strain of penicillin (isolated from a mouldy melon) increased yields 20-fold. By late 1943 mass production of the drug had begun in America using a deep tank fermentation process which was much more effective than the two-dimensional fermentation in thousands of bottles or flasks undertaken previously.

After the excitement of penicillin the rest of Heatley's career could have seemed something of an anticlimax, but his genius for introducing new methods and refining and miniaturising existing ones remained and the results, many of them collaborations with a wide range of scientists, are described in the 60-plus scientific papers he wrote or co- authored. In retirement he loved to spend time in his garden shed, inventing new gadgets and solving domestic problems.

In 1992 an annual Norman Heatley Lecture was set up at Oxford by Robert Marston, a former Rhodes Scholar and Heatley student who became Director of the US National Institutes of Health and President of Florida University; the two most recent lectures were given by the Nobel prizewinners Tim Hunt and Sydney Brenner. Heatley is further remembered in the name of a road in Oxford's new science park in Littlemore.

Outside his work he was a quintessential family man - a proud and immensely involved father, an affectionate husband, an accomplished house husband, an excellent host. His practical brilliance was matched by his down-to-earth, sometimes impish, good-humour. He was an excellent raconteur and very good company.

His home in Old Marston was, for over 50 years, a welcoming haven for generations of students and scientists working in Oxford.

Eric Sidebottom