The Oxford Science Lecture Series

Professor  Susan Lea

University of Oxford

“Bacterial secretion systems - using structure to build towards new therapeutic opportunities”

Dorothy Hodgkin Memorial Lecture 2013

University Museum, Oxford, 5th March 2013

The 2013 Dorothy Hodgkin Lecture was given by Prof. Susan Lea from the Dunn School of Pathology in Oxford. Professor Lea studied pre-clinical medicine at Oxford and went on to do a DPhil and post-doctoral research in Biochemistry. She was awarded a Royal Society Dorothy Hodgkin Research Fellowship which enabled her to establish herself as an independent scientist, for which she is extremely grateful. She is now Professor of Chemical Pathology and co-director of the Oxford-Martin Programme on Vaccines.

Professor Lea began her lecture by showing Rembrandt’s painting ‘The Anatomy Lesson of Dr.Nicolaes Tulp’, commenting that in medicine it is easy to understand something if you can see it. However biology involves the study of much smaller entities than can be seen by eye, or even using a microscope, as bacteria are 0.5-1 microns in size and DNA is 2 nanometers across. Furthermore, what biologists are often interested in are the interactions between proteins, which are even smaller, but can be understood using the techniques of x-ray crystallography developed by Dorothy Hodgkin . Early in her career, Professor Lea met Dorothy Hodgkin at a conference in China where Dorothy grilled all the graduate students about what they were doing in their studies , and why they were doing it!

Professor Lea explained that proteins can be represented in a number of different ways, as atoms and bonds, as ribbon structures which show the ways a protein folds, or as a surface coloured to show distribution of charges. These different types of information can suggest the function of the protein and how it interacts with other structures in a system. In her research, Professor Lea is looking at how pathogens work, with the aim of developing new therapeutic molecules. Penicillin works by attacking the bacterial cell wall, and as mammalian cells don’t have a cell wall this makes its mode of action specific to bacteria. By understanding how proteins interact within pathogens, other processes unique to the pathogen may be identified and used to develop novel therapeutics.

Dysentery results in 1.1 million deaths per year and can be caused by a bacterium called shigella flexneri . This bacterium has a protein secretion system called the type 3 secretion system which is found in many particularly nasty bacteria. In this system, the bacterium assembles proteins to form a gateway out of the cell connected to a long tube. When the bacterium encounters a colon cell it secretes proteins which punch a hole in the colon cell and thereby allow toxic molecules to transit from the bacterium into the colon. Professor Lea explained that by using electron microscopy and x-ray crystallography, they could see that the needle structures had a helical shape. However, the proteins that are transported down this needle are much larger than the calculated diameter of the tube, so they must unwind their structure to slide down the tube and then re-fold at the other end. Profesor Lea’s group has also investigated the end of the needle structure and found that it can be open or closed. As yet, they don’t know what causes the needle to open, but if they could find a molecule that inhibited that process, they would prevent the bacterium from acting. They also found that where the needle breaks through the cell membrane there is a ring of nine proteins and if the inner surface of this ring is modified then secretion is stopped. The hole in the membrane is big enough to hold a folded protein, but above it in the needle is a cage-like structure which might be what prompts the protein to unfold. Professor Lea concluded by saying that the investigation of the structure of the proteins in the delivery system had provided valuable insights into how this lethal bacterium delivers its toxic cargo and had generated several possible targets for drug development.

The evening concluded with questions, after which the audience and speaker enjoyed a glass of wine in the gallery of the museum.

Dr Carolyn Carr

Cardiac Metabolism Research Group, University of Oxford