Tailor-made sugar coated proteins manufactured in novel E. coli system

November 28, 2002

The prospect of using bacteria to manufacture complex human proteins for use in therapeutic drugs is a step closer thanks to new research published today in Science.

Researchers from Switzerland and the UK report they have engineered the bacterium Escherichia coli to carry a vital piece of cell machinery that adds sugar molecules to newly synthesized proteins by a process known as glycosylation.

The finding opens up the possibility of producing complex human proteins such as Factor VIII and the hormone erythropoietin, which stimulates the production of red blood cells by stem cells in bone marrow. Both these proteins, which require the addition of sugar molecules to function properly, are currently produced by culturing mammalian cells, which can be a costly and technically difficult process.

The addition of sugars to proteins by glycosylation is crucial in defining their job in the body by helping them fold into a particular three-dimensional shape that determines how they interact with other proteins.

Simple bacterial cells normally do not possess the same type of cellular machinery used for glycosylation in higher organisms like humans. Until now this has restricted the types of human proteins that can be produced in bacteria.

The team of scientists from the Swiss Federal Institute of Technology, Zurich, the London School of Hygiene and Tropical Medicine and Imperial College London have shown that the bacterium Campylobacter jejuni uniquely contains glycosylation machinery similar to the type found in higher organisms. They have developed a technique of transferring this machinery into the E. coli bacterium, which is widely used in the industrial production of proteins.

Professor Anne Dell of Imperial College London said:

"We are only now beginning to understand the vital biological role sugars play in monitoring and guiding the day-to-day lives of the cells in our bodies. This work opens a path for the production of tailor-made glycoproteins in high abundance for applications in research and industry."

Using new high sensitivity mass spectrometers housed in the Department of Biological Sciences together with facilities in the M-Scan Mass Spectrometry Research and Training Centre, Ascot, the Imperial research team headed by Professor Dell and Professor Howard Morris were able to identify the precise nature of glycosylation in C. jejuni, including the exact position where sugars are attached to proteins.

Colleagues in Zurich were then able to insert the C. jejuni glycosylation machinery into E coli and test whether it worked using mutational analysis.

"We have only begun to scratch the surface in understanding important role sugars play in our body," said Professor Dell. "Many common diseases including certain types of rheumatoid arthritis and muscular dystrophy have already been linked to disruption of the delicate balance of sugars displayed on the surface of proteins. Deciphering these complex interactions will be significantly aided by the new tool our research has developed."

Professor Brendan Wren of the London School of Hygiene and Tropical Medicine added:

"C. jejuni is recognised to be the major bacterial cause of gastro-intestinal diseases worldwide and can lead to the development of serious neurological disease. Despite the importance of the organism it is very poorly understood. Apart from its potential in glycoengineering, the newly characterised glycosylation system will also be useful in the development of vaccines to reduce the burden of Campylobacter-related disease".
The Imperial College London research infrastructure was funded by a JIF grant, which involves partnership between the Wellcome Trust, the Office of Science and Technology and the Higher Education Funding Council for England. Additional support was provided by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust. Professor Anne Dell currently holds a BBSRC Professorial Fellowship.

For further information, please contact:

Judith H Moore
Imperial College London Press Office
Tel: +44 (0)20 7594 6702
Mobile: +44 (0)7803 886 248
E-mail: j.h.moore@imperial.ac.uk

Lindsay Wright
London School of Hygiene and Tropical Medicine Press Office
Tel: +44 (0)20 7927 2073
Email: Lindsay.Wright@lshtm.ac.uk

Notes to editors

Journal: Science

Title: "N-Linked Glycosylation in Campylobacter jejuni and Its Functional Transfer into Escherichia coli" Science (29 November 2002)

Authors: Michael Wacker (1), Dennis Linton (2), Paul G Hitchen (3), Mihai Nita-Lazar (1), Stuart M. Haslam (3), Simon J. North (3), Maria Panico (3), Howard R. Morris (3,4), Anne Dell (3), Brendan W. Wren (2), Markus Aebi (1)

1. Institute of Microbiology, Department of biology Swiss Federal Institute of Technology, Zurich, CH 8092 Zurich, Switzerland.

2. Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Disease, London, WC1E 7HT, UK

3.Department of Biological Sciences, Imperial College London, SW7 2AZ, UK

4. M-SCAN Mass Spectrometry Research and Training Centre, Silwood Park, Ascot, SL5 7PZ, UK

About the Swiss Federal Institute of Technology Zurich

The name is known throughout the world: The Swiss Federal Institute of Technology Zurich is a science and technology university with an outstanding research record. Excellent research conditions, state-of-the-art infrastructure and an attractive urban environment add up to the ideal setting for creative personalities. 20'000 people from Switzerland and abroad are currently studying, working or conducting research at ETH Zurich. ETH earned its excellent national and international reputation through major achievements in research as well as through first-rate teaching and services.

About London School of Hygiene and Tropical Medicine

The London School of Hygiene and Tropical Medicine is a renowned research-led postgraduate medical school with a unique mission to contribute to the improvement of health worldwide through the pursuit of excellence in research, post graduate teaching, advanced training and consultancy in international public health and tropical medicine. As it enters its second century the School's commitment to excellence and its leadership role in these subject areas has never been more evident.

About Imperial College London

Consistently rated in the top three UK university institutions, Imperial College London is a world leading science-based university whose reputation for excellence in teaching and research attracts students (10,000) and staff (5000) of the highest international quality.

Innovative research at the College explores the interface between science, medicine, engineering and management and delivers practical solutions, which enhance the quality of life and the environment - underpinned by a dynamic enterprise culture. Website: www.imperial.ac.uk

Imperial College London

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