From Bugs To Drugs

COMMERCIAL PROFILE -  SCIENCE FOUNDATION OF IRELAND:New molecular methods means we can learn about bacteria without having to grow them, paving the way for a new range of therapies

TREATMENTS FOR hospital "superbugs", natural anti-inflammatory drugs, and therapies for conditions such as irritable bowel syndrome and colitis are just some of the potential benefits of the Cork based Alimentary Pharmabiotic Centre (APC) - a gastrointestinal health research centre and partnership involving UCC, Teagasc and industry partners, Alimentary Health Limited and GlaxoSmithKline.

The centre is one of 10 Science Foundation Ireland (SFI) funded Centres of Science, Engineering and Technology (CSETs) in Ireland, and was launched in 2003. The research undertaken at the APC focuses primarily on the area of gastrointestinal health. In late 2008 the centre was approved second term funding of more than €17 million from the Government through the SFI CSET programme with industry contribution, to support its research programme for a further five years. In the period since its establishment the centre has grown into a 100-strong multi-disciplinary research team with a variety of funding sources, with staff based at both UCC and Teagasc's Moorepark Food Research Centre.

The human body contains 10 times more bacterial cells than human cells. These bacteria are primarily found in the gastrointestinal (GI) tract. This has given rise to the concept of the human as a 'super-organism', in which the complex interaction between these two cell populations plays a very important role in human health. Most of these bacteria have never been grown in laboratories, and their very existence is only known through sophisticated DNA diagnostic techniques.

According to APC director Professor Fergus Shanahan the first five years of the centre's work was mainly involved in prospecting while the next phase will involve exploiting this work to develop novel new therapies and other commercial applications such as probiotic foods. "In the first five years we did a lot of work on identifying what kind of bacteria were in the gut - now we want to mine them and exploit them for novel drug discovery among other things", he explains.

"The pharmaceutical industry has been developing drugs from bacteria in the soil for many years", he continues. "Now we want to look at the human environment. The gastro-intestinal tract is regarded as the last great neglected organ - if you put all the bacteria in it together you would get an organ the size of the liver and we are now studying that."

This hasn't been done before now due to technological limitations. "Up until recently the only way we could study bacteria was by growing them and studying them in a laboratory", Shanahan points out. "But only 20 per cent of the bacteria in the gut can be grown under laboratory conditions: 80 per cent of them can't be cultured."

The inability to grow these bacteria makes it difficult to identify the properties that allow them to adapt to the harsh conditions of the GI tract and thus to influence human health and disease.

"Look at the helicobacter bacteria, which causes ulcers in many people, for example. This lives in acid. Some people call organisms like this 'extremeophiles' because of the conditions they live in. C. difficile is another example. It's called difficile because it was so difficult to grow outside of the gut."

A new approach known as metagenomics has overcome this problem. This allows identification of individual bacterial genes without ever having to grow the bacteria. "These new molecular methods allow us to learn about the bacteria and what they do without having to grow them", says Shanahan. "And this is what is bringing us to the second phase of our work which we call bugs to drugs."

Among the more interesting aspects of the centre's work is using existing knowledge to develop new therapies. "We can already predict lots of things about bacteria," he says. "For example, we know that the bacteria population in the gut is got at controlling its numbers. The number is quite stable in the absence of disease. It is therefore likely that it must produce its own chemicals or antibiotics to keep the numbers under control. One of the things we have been doing is looking to identify these chemicals and we have found the one that controls C.difficile (see panel)."

New drugs are not the only benefits that will arise from APC's research efforts, however. "There is a big nutritional side to it too," Shanahan points out. "We have germ-free animals such as lab rats and so on who are bred and kept in sterile environments. We know from these animals that they require between 20 per cent and 30 per cent more food than normal to maintain their body weight. This shows the important role that bacteria plays in the digestive system in terms of making vitamins and contributing calories. It should be possible to mine these bacteria and make them work more efficiently for us."

These could be used in foods with health giving properties known as functional foods. "This is a hot area and a huge area of commercial interest at the moment," he says. "But it is just part of what we are doing here.

"At another level we are trying to create an environment that's conducive to innovation," he adds. "You can't create innovation - you can create the right environment for it and remove the barriers to it. Over the next five years we will be challenged again to be an agent of change. In large part we have already been successful, in that 10 years ago many scientists didn't think about the commercial applications of their research and that is an important area of our work here."

The partnership with GlaxoSmithKline is very significant in that respect. "When GlasxoSmithKline came on board it was because they saw that we had a critical mass in this area," he explains. "The pharmaceutical industry has been finding it difficult to come up with new blockbuster drugs over the past number of years and are now coming to research centres like APC to outsource their research. GlaxoSmithKline has crossed that philosophical Rubicon more than most and is partnering with us in the research. This is important as it means we have Irish minds working on leading-edge research, innovation and commercialisation in this area."

Looking to the future he believes that new commercial breakthroughs will flow from APC over the coming five years. "If we get the luck we deserve for the hard work we have put in we should see a number of important new developments over the next five years."

Tackling the superbugs

CLOSTRIDIUM DIFFICILEhas moved from relative obscurity to being a notorious hospital "superbug". Healthy people can harbour C. difficilewithout ill effects. However, those on antibiotics can experience disturbances in the balance of bacteria in their gut, which allows C. difficileto proliferate and produce two potent toxins which cause symptoms ranging from mild diarrhoea to a life- threatening condition known as pseudomembranous colitis(PMC).

The elderly and people with impaired immune function are particularly susceptible. C. difficilecan survive for long periods in the environment and is extremely persistent in locations such as hospitals and nursing homes. APC scientists are investigating bacteriocins (small proteins produced by one bacterium that kill other bacteria) as alternatives to the currently used antibiotics, vancomycin and metronidazole. Human faecal samples were screened for bacteria that would produce anti-microbial compounds which would kill C. difficilewithout affecting the beneficial bacteria in the gut. Of 30,000 bacterial colonies screened, one was found to produce a potent anti-microbial compound.

This bacteriocin inhibits all C. difficile strains tested to date, including those associated with C. difficile-associated disease. Studies have shown that this compound does not affect other non-harmful gut bacteria. Work is ongoing at APC to assess the potential of the bacteriocin as a novel new treatment of C. difficileassociated disease.