Could a crocodile save your life?

While making a TV documentary, a team of researchers made a remarkable discovery. Wild crocodile blood may help the world to beat bacteria
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The Independent Online

Two television producers set out to make a film about crocodiles. Several months later, after much derring-do in the Australian outback hunting crocs, they returned with more than just a roll of videotape. They also brought back samples of crocodile blood that might, just might, provide the world with a new kind of antibiotic.

Two television producers set out to make a film about crocodiles. Several months later, after much derring-do in the Australian outback hunting crocs, they returned with more than just a roll of videotape. They also brought back samples of crocodile blood that might, just might, provide the world with a new kind of antibiotic.

With the help of a scientist in the US, they analysed the blood and found it contained a unique agent which plays a key role in the crocodile's defence against infection. If the agent lives up to its initial promise and can be developed for human use, it could one day help tackle the global problem of antibiotic resistance. They have called it Crocodillin.

These are big ifs, of course. Thousands of compounds show promise in early tests only to fall at one of the many hurdles they must pass before winning a licence and a place on the market. But the story of Crocodillin - how it was discovered and why it might work - is worth telling because it is one of a new class of drugs, called anti-microbial peptides, which are being intensively studied, and which could revolutionise the treatment of infection.

The story begins on a crocodile farm in Australia. The BBC had decided it wanted a film on crocodiles and asked Jill Fullerton-Smith, an experienced producer, to come up with ideas. Ms Fullerton-Smith contacted crocodile expert Adam Britton, a British scientist living in Australia who has devoted his life to studying the dinosaurs of the modern age. Initially, Mr Britton suggested a good subject for the film would be new research being done on vocalisation - how crocodiles talk to each other.

"That is his passion," said Ms Fullerton-Smith. "But, in passing, he happened to mention that one of the odd things about crocodiles is how they attack each other and tear limbs from each other and then sit in filthy, bacteria-laden water and despite their injuries they heal."

The observation hovered in the back of her mind for some weeks. She mentioned it to assistant producer Chloe Leland, who has a degree in biology. Slowly it dawned on the pair that there was a question here that demanded an answer. How could a creature with horrific injuries - and the savagery of crocodiles is notorious - heal in bacteria-filled water without the benefit of antibiotics? Why did they not succumb to infection?

Ms Leland began the search for an answer. Was anyone working on the immune system of the crocodile? She drew a blank and at that point the pair almost abandoned the project. Then they came upon a report of research on the immune response of the frog.

That led them to the laboratory of Gill Diamond, a scientist at New Jersey Medical School in the US who was working on the Komodo dragon. They discovered there was intense interest in anti-microbial peptides and what is known as the innate immune system.

The innate immune system is little discussed. It is distinct from the acquired immune system, which is built up from birth, in that it has been present from the dawn of time. The acquired immune system consists of cells and antibodies "trained" to attack specific targets. The innate immune system is however the first line of basic defence that protects us from infection by the bacteria. It includes at the simplest level the outer barrier of the skin, for example, the acid in our stomachs which destroys bacteria in food. The innate defence also includes anti-microbial peptides - short proteins - that can attack invading micro-organisms in the mucous lining of the lungs.

"It is a non-specific first line of host defence," says Dr Diamond. If the invading bacteria penetrate the first line of defence, then the acquired immune system comes into play, recognising the invader, making antibodies to attack it which in turn trigger a fever.

The unique feature of the innate immune system is that, being non-specific, it attacks everything - using a mechanism that involves punching holes in the membranes of the bacteria. The system was so primitive that scientists had dismissed it, but its virtue in an age of antibiotic resistance is that it is very difficult for bacteria to become resistant to it.

Furthest advanced in the exploitation of the innate immune system is Magainin Pharmaceuticals, a US biotech company that has been developing a drug based on an anti-microbial peptide taken from the frog for seven years. Called Locilex, it is a cream for diabetic foot ulcers, which are notoriously difficult to treat, and has reportedly shown benefits over existing antibiotics. It has completed Phase Three clinical trials but the US Food and Drugs Administration was unhappy with aspects of the trial design and has yet to grant it a licence.

Dr Kenneth Holroyd, the senior vice president for research at Magainin, said the company was discussing with Smith Kline Beecham, the multinational company which has agreed to market the drug once it is licensed, how to proceed. "We are still optimistic the product will be approved," he said.

For Chloe Leland and Jill Fullerton-Smith, this was the green light. "There was so much interest in anti-microbial peptides we decided to look there. And we thought the whole story of the innate immune system was fascinating - it had outlived the dinosaurs," said Ms Leland.

They set out to collect blood samples, which proved to be an even trickier task than expected. They started with the crocodile farms across Australia, but the blood from the farmed crocs turned out to be useless. Tame crocodiles living on an artificial diet might have different immune systems and might not face the variety of bacteria they would encounter outside the farms. They needed wild crocodile blood.

There followed several forays into the swamps by night, the intrepid hunters in one boat carrying harpoons tipped with sedative drugs to catch their prey and subdue it long enough to obtain the samples, while the television crew followed in a second boat. Their escapades, including one occasion when an angry croc ripped a hole in the side of the boat which then began to sink, are recorded in a dramatic film to be shown on BBC1 next week.

There were several false starts. One set of samples went missing and another was not refrigerated properly. When, at the third attempt, Dr Diamond received a usable supply of crocodile blood, he separated it into racks of test tubes to analyse its components. These were then tested against samples of bacteria by placing a drop in the centre of a petri dish. Test tube 13 came up trumps.

Dr Diamond said: "The researcher came in early and found it had cleared a large spot in the centre of the dish. She was sufficiently impressed to phone me at home to tell me the good result." Dr Diamond was delighted with the discovery and it was he who named the new agent Crocodillin. Exploiting it, however, will take time and money, neither of which is currently forthcoming. "The BBC came up with the initial funds, but it is not really in the business of drug discovery," Dr Diamond said. The new agent is, for the time being, sitting on a laboratory shelf.

While lawyers negotiate over who owns the intellectual property rights to the discovery, Dr Diamond is convinced anti-microbial peptides offer one of the most hopeful answers to the problem of antibiotic resistance. The peptides are found in most species, including humans, cows and fish, as well as frogs and now crocodiles, but their role in combating infection has, until now, been overlooked.

He said: "The whole field is very good because research groups are reporting new types of antibiotic. At least four drugs based on anti-microbial peptides are in development. Bacteria don't seem able to develop resistance to them in the way they do to conventional antibiotics. But the Food and Drugs Administration wants to tread very lightly. Once the first new drug is approved it could open the floodgates."

'The Secret Life of Crocodiles', BBC1, 8pm, Wednesday 31 May

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