The Oxford Science Lecture Series

PROFESSOR LOUISE JOHNSON

David Phillips Professor of Molecular Biophysics, University of Oxford

"Dorothy Hodgkin and penicillin - 50 years from structure to present day understanding of biosynthesis and bacterial resistance"

Dorothy Hodgkin Memorial Lecture 1999

University Museum, Oxford, 4th March 1999

Professor Louise Johnson FRS, David Phillips Professor of Molecular Biophysics at Oxford University, gave the first Dorothy Hodgkin Memorial Lecture at Oxford's Museum of Natural History on 4 March. Entitled "Dorothy Hodgkin and penicillin - 50 years from structure to present day understanding of biosynthesis and bacterial resistance", the lecture was organised by the Oxford International Women's Festival with the support of Oxford AWiSE and Somerville College.

Dorothy Hodgkin remains the only British woman scientist ever to have won a Nobel prize. She won it for her x-ray cyrstallographic studies of important biological molecules, mainly penicillin and Vitamin B12, and went on to lead the team that solved the structure of the hormone insulin. Professor Johnson never worked directly with her, but came to know her well when she worked on similar problems in an adjacent laboratory at Oxford; like Professor Hodgkin, she too became a Fellow of Somerville College. For her lecture she chose to focus on penicillin, to mark the 50th anniversary of the first publication of its structure, and because modern structural biology is still playing an important role in the fight against infectious disease.

She began by recalling Alexander Fleming's accidental discovery of the penicillium mould's lethal effect on bacteria in 1929, and his failure to capitalise on that discovery. The story then switched to Oxford, where ten years later Professor Howard Florey and Ernst Chain in the Sir William Dunn School of Pathology were beginning to look at a variety of naturally-produced chemicals that could kill bacteria. Florey's assistant, Norman Heatley solved the problem that had stumped Fleming, that of extracting the penicillin from the mould, and they went on to conduct a dramatic experiment. Florey injected eight mice with lethal doses of streptococci, and then dosed four of them with penicillin. All the untreated mice were dead withing 16 hours; those that received penicillin survived for days to weeks. Successful trials on human patients quickly followed.

Dorothy Hodgkin's role in the story was to solve the three-dimensional stucture of the penicillin molecule at a time when its chemical formula was still the subject of much debate. It was the largest molecule ever to have been solved by x-ray methods at the time. The crucial part of the molecule turned out to be the four-membered beta-lactam ring. Professor Johnson explained how this structure enables the drug to target bacteria very specifically, while having no effect on human tissues. It interferes with the construction of bacterial cell walls, interacting with an unusual 'right-handed' form of amino acid, and so prevents the bacteria from multiplying.

Although at the time chemists hoped that Dorothy's solution of the penicillin structure would make it possible to produce the drug synthetically, in fact fermentation of the mould still plays an important part in penicillin production. Professor Johnson explained that it was only in the past few years that researchers in the Dyson Perrins Laboratory at Oxford had solved the structure of the enzyme isopenicillin synthase and uncovered the complex sequence of steps by which the penicillium mould makes penicillin.

She went on to bring the story right up to date, presenting the stark realities of antibiotic resistance. Because of over-use and failure to complete the courses prescribed, penicillins and many other antibiotics have now become virtually useless in many parts of the world as resistant strains of bacteria have gained the upper hand. She explained how researchers and bacteria were now locked in an 'arms race' as each tried to overcome the weapons of the other. Many bacteria secrete an enzyme called beta-lactamase, which disables the penicillin molecule before it can enter the bacterial cell. Using the latest versions of the x-ray techniques applied with such skill by Dorothy Hodgkin, structural biologists have discovered the structure of this enzyme and other proteins that play a role in penicilin's interaction with bacteria, and are now exploring ways of undermining bacterial defences so that antibiotics can do their work. The approach, said Professor Johnson, was like that of visitors to the underworld in the ancient Greek legend, who had to throw a cake into the jaws of the guard dog Cerberus to give them time to slip past.

Professor Johnson left her own work to the end of the lecture. She and her colleagues have now turned their attention to the natural but uncontrolled processes that turn normal cells into cancers. Cancers are a much more difficult target than bacteria, because of the risk that treatments will also damage normal, healthy tissue. The molecules she is investigating are enzymes - protein kinases - that alter other proteins during the cell's cycle of growth and reproduction. Humans have up to 2000 different kinds of these enzymes, and the challenge is to find drugs that can inhibit one or more of them very specifically. Using a series of computer-generated images, Professor Johnson showed how once again, structural studies are playing an important part in revealing the complex interplay of molecules in health and disease.

She concluded with a slide showing Dorothy Hodgkin beaming with characteristic delight in front of a model of the enzyme lysozyme, the first enzyme structure to be solved. Professor Johnson had worked on this structure as a young PhD student in the laboratory of Professor David Phillips (who sadly died only a few days before the lecture). As the Principal of Somerville College Dame Fiona Caldecott said in her vote of thanks, Professor Johnson's talk showed that she shared the same delight and enthusiasm for her subject as Dorothy Hodgkin.

Georgina Ferry.