Obituary: Sir Edward Abraham

EDWARD ABRAHAM, Emeritus Professor of Chemical Pathology at Oxford University, devoted his scientific career to the study of antibiotics. His outstanding achievement was the discovery of the Cephalosporin group of antibiotics.

He was educated at King Edward VI School, Southampton, and Queen's College, Oxford, where he read for the Honours School of Natural Science and took a First in Chemistry. His postgraduate research in the Dyson Perrins Laboratory led to his DPhil's being awarded in 1938, after which he won a Rockefeller Foundation Travelling Fellowship and went to Stockholm.

He returned to Oxford just before war was declared to accept the invitation of Professor Howard Florey (later Lord Florey) to join the team of scientists at the Sir William Dunn School of Pathology undertaking a study of antibiotics. The main goal of the team was to isolate penicillin in sufficient quantity to enable its efficacy to be demonstrated in man. While Florey and Norman Heatley focused on the in vivo activity and clinical aspects of the antibiotic, Ernst Chain and Abraham were studying its molecular structure.

The hope was that if the structure could be elucidated the molecule might be chemically synthesised in sufficient quantity to meet the needs of the armed forces. The study of penicillin during the Second World War was a monumental Anglo-American scientific collaboration. Two scientists independently deduced the correct structure for penicillin, one was Edward Abraham, the other Robert Burns Woodward.

The structure they proposed was later independently confirmed by Dorothy Hodgkin using X-ray diffraction of crystals of the sodium salt. The penicillin structure, however, was a highly functionalised and fragile molecule, so that, in spite of many attempts, total chemical synthesis remained elusive until the end of the 1950s.

It was during the early 1950s that the attention of a British Medical Officer in Sardinia was drawn to the work of Professor Giuseppe Brotzu, the Rector of the University of Cagliari. He had discovered a micro-organism in the sewage outfall off the coast of Sardinia which when grown in culture produced a substance which had antibacterial properties similar to penicillin. A letter was sent to Florey to ask if he would be interested in investigating this new fungus. The micro-organism was duly sent to Florey who invited Abraham to investigate it.

The fungus was identified as a Cephalosporium species. Abraham with his colleague Guy Newton quickly identified the effective antibiotic as penicillin N. The micro-organism, however, produced many weakly active antibiotics but one, referted to as Cephalosporin C, because it was the third component to emerge from the fractionation of the aqueous extract, attracted Abraham's attention. Although the substance was only weakly active it was not destroyed by penicillinase, an enzyme known to be capable of causing bacteria to become resistant to penicillin.

Indeed, as early as 1940, Abraham and Chain had published a paper in Nature showing the existence of penicillinase in bacteria and Abraham was deeply conscious of the threat of the spread of this resistance factor. His prescience led him with his colleague Newton to focus their attention on Cephalosporin C in spite of the difficult task of isolating this rather unstable, water-soluble substance. Cephalosporin C was isolated and its structure elucidated largely by classical degradative methods.

He was at first reluctant to publish the structure because the ultraviolet spectrum was unprecedented, but after accepting an invitation to an international congress in the early 1960s to speak about Cephalosporin C he was persuaded that he could not describe the degradative evidence without divulging his conclusions about the structure. He was of course correct and again it was Dorothy Hodgkin using X-ray crystallography who later confirmed the structure he had proposed.

Recognising the loss of revenue to the UK by the Medical Research Council's declining Florey's proposal to patent penicillin, the Government set up the National Research Development Corporation in 1949 to provide a mechanism for the licensing of intellectual property. The NRDC which was in part supporting the work on Cephalosporin C was quick to make the most of this discovery.

In order to strengthen the patenting position a remarkable series of experiments were undertaken which allowed the side chain of Cephalsporin C to be removed (in extremely low yield) and replaced with one which they judged would greatly enhance the activity. It did, by more than a hundredfold, and so they could claim in the patent the key compound 7-amino-cephalosporanic acid, the nucleus of the antibiotic.

From this key intermediate literally thousands of cephalosporins were made over the next two decades largely by the British, American and Japanese pharmaceutical industry. Cephalosporin C had a second site which Abraham and Newton showed could be substituted with a variety of groups.

With two sites for substitution a huge variety of cephlosporins could be made, several quickly establishing themselves in the clinic. Many possessed a broad spectrum of anti-bacterial activity and became front-line drugs in the treatment and prevention of bacterial infection. The NRDC made very favourable royalty and information transfer arrangements with overseas pharmaceutical companies.

The royalties from Cephalosporin C which flowed into the NRDC sustained it over its first two decades. Three Charitable Trust Funds were set up by Abraham to receive his royalties from which the university and many of Oxford's colleges and departments have benefited enormously. Many a young scientist has cause to thank Edward Abraham for providing so many junior research fellowships in Oxford colleges. The university benefited from the endowment of several chairs as well as from funds for the building of new laboratories. The Royal Society benefited from the endowment of the EPA Cephalosporin Fund Senior Research Fellowship.

The Chair of Pathology in Oxford is associated with a Professorial Fellowship at Lincoln College and Florey was able to raise endowment from Lord Nuffield in the 1940s for three research fellowships at the college. Abraham was an original recipient of one of these and remained a Fellow of Lincoln from 1948 until he retired in 1980, when he became an Honorary Fellow. He enjoyed participating in college life and played an active role on the college's governing body.

He received many honours during his lifetime, including Honorary DSc degrees from Oxford, Exeter and Strathclyde. He was elected to the Fellowship of the Royal Society in 1958 and was awarded the Royal Medal (1973) and the Mullard Medal (1980) of the society. He was appointed CBE in 1973 and knighted in 1980. After his retirement he remained active in his research and continued his collaboration with Sir Jack Baldwin on the biosynthesis of the penicillins and cephalosporins. He also retained a particular interest in the running of the trust funds.

Edward Abraham was a gentle and kindly man who attracted to Oxford many eminent scientists. He modestly claimed that he had been lucky in his research, but those who knew him well recognised that the light shone brightly on that prepared and receptive mind. Few would have recognised the significance of that weakly active fraction produced by a micro-organism from the sewage outfall off the coast of Sardinia and pursued it with such tenacity.

With his wife, Asbjorg, he frequently travelled to her native Norway, where they had a mountain chalet from which they loved to ski and walk. They were also enthusiastic gardeners and delighted in showing visitors around the extensive and immaculately kept garden at their home on Boars Hill.

Edward Penley Abraham, chemist: born Southampton 10 June 1913; Fellow, Lincoln College, Oxford 1948- 80; FRS 1958; Reader in Chemical Pathology, Oxford University 1960-64, Professor of Chemical Pathology 1964-80 (Emeritus); CBE 1973; Kt 1980; married 1939 Asbjorg Harung (one son); died Oxford 8 May 1999.