Gastric ulcers, caused by the Helicobacter pylori bacterium, pose a huge public health problem: in the developing world 80 per cent of people suffer from this painful and debilitating condition at some point in their lives, and 30-40 per cent of people in the developed world will be affected. Worse still, H. pylori infection also increases the risk of gastric cancer.

Dividing his time between two London institutions, Birkbeck College and University College London (UCL), Professor Gabriel Waksman is investigating the mechanism by which H. pylori causes disease in the human gut.

The chief culprit appears to be a bacterial protein known as CagA - not all strains produce it, but those that do are more dangerous and more likely to cause cancer. This protein is secreted by H. pylori and recruits other proteins to form a large complex, which attaches to the cells of the gut wall. In doing so, CagA alters the way in which human gastric cells respond to their environment. Chemical signalling pathways inside cells are derailed, leading to the disease state or ulceration - and, in some cases, uncontrolled proliferation of cells.

To address this problem it is therefore important to understand how CagA is transported out of the bacterium. "If you can prevent the CagA getting out," says Professor Waksman, "you’ve got a cure for ulcers."

Professor Waksman is concentrating on the molecular machinery responsible for CagA secretion - the so-called type IV secretion systems, which work in similar ways to a pump. "They have many components," explains Professor Waksman. "It’s a large machinery with several parts. What we want to do is determine exactly the structure of each of these parts or proteins."

Professor Waksman and his team are using X-ray crystallography to examine each component in detail. The first step is to use classical biotechnology to produce large quantities of the proteins in genetically engineered bacteria. "Then we grow crystals of the different proteins. With rapidly developing technology the pace at which we can do so has increased dramatically: it now takes weeks, rather than months, to grow crystals of a protein."

The crystals are then bombarded with X-rays. Most pass through the crystals but some are diffracted when they encounter atoms of the protein. By looking at the patterns of diffraction, researchers can deduce the three-dimensional structure of the protein. "This is the main contribution of X-ray crystallography," says Professor Waksman: "the power of seeing."

The objective of the structural work is to gather clues about the function of the different components - to gain a picture of how they work in unison to transport material. "Once we understand how these secretion systems work, we can tailor them to our own needs. We can design interventions to prevent them secreting disease-causing toxins - or we can encourage them to secrete specific transforming proteins that work to our advantage."

Professor Waksman and his team have determined two structures in the early stages of the programme. Intriguingly, these reveal a structural relationship similar to the transport system found inside human cells, in which proteins are shuttled in vesicles from one cellular compartment to the next. Possibly, bacterial type IV secretion system might be an ancestor to the more sophisticated system of transport found in humans.

In the longer term, this work could have implications far beyond Helicobacter pylori and gastric ulcers, important though they are. Type IV transport systems are widely distributed through the bacterial world, and have been adapted to serve a wide range of needs. Agrobacterium tumefaciens, for example, uses them to transfer DNA to plants, which are diverted into making galls in which the bacteria can thrive. Agrobacterium has long been a favourite of the biotechnology industry, as its ability to deliver DNA into cells has been used to change the genetic make-up of plants - and it has thus underpinned the genetically modified food industry.

Transfer of DNA through type IV transport systems also has major medical implications. For example, it is also thought to contribute to the growing problem of antibiotic resistance. Type IV secretion systems not only transport toxins out of the bacteria, but can also export plasmid DNA containing genes encoding antibiotic-degrading enzymes - a significant cause of antibiotic resistance. "An important long-term aim of this research is that it will be helpful in designing novel interventions to beat antibiotic resistance, by finding ways to prevent plasmid DNA being transported out of the bacterium," explains Professor Waksman.

As a step towards this future goal, he is setting up an Institute of Biomolecular Sciences jointly at UCL and Birkbeck, which will unite the Biochemistry Department at UCL with the Crystallography Department at Birkbeck. The Institute will regroup researchers in the fields of structural biology and bioinformatics, providing important synergies. The structures of medically important proteins worked out using powerful X-ray crystallography technology at Birkbeck could then be exploited for drug design by biochemists at UCL. From such collaboration could emerge new approaches to pump inactivation - or even the use of bacterial pumps to deliver medically useful materials into cells.

See also

• Professor Gabriel Waksman at the School of Crystallography, Birkbeck College London: Research interests