Frog is a friend in search for cure

November 30, 2001

Geoff Watts reports on the Ulster academic who is 'milking' frogs in his search for a new generation of drugs.

In recent years we have witnessed a succession of adventurous academic scientists trooping into jungles in search of plants or fungi that might be producing molecules with potential value in medicine. Rather fewer have gone in search of animals that can perform the same trick. One of this handful of more zoologically inclined seekers is Chris Shaw, head of pharmaceutical biotechnology research at the University of Ulster. And the animal he is after? The frog.

The realisation that amphibians might have something to offer drug research is all down to the Italian pharmacologist Vittorio Erspamer, the man who discovered the brain chemical serotonin. Credit should really go to Erspamer's dog. "Erspamer had a summer house in the hills above Rome," Shaw explains.

"He was sitting in a deckchair one day when his dog pulled a toad from under the hedge. A few minutes later the dog began writhing about on the ground, totally incapacitated."

Intrigued, Erspamer began studying the venom secreted by glands in the skin of toads. He discovered that they contained a cornucopia of chemicals that had marked effects on animal tissue. Moving on to frogs, he found that their skin too resembled a chemical manufacturing plant - in this case making small protein molecules or peptides.

With a background in hormonal influences on the nervous system, Shaw was well placed to set up some experiments. A few years ago, while working at Queen's University, Belfast, he analysed extracts of frog skin and found that each species makes a vast number of peptides: up to 1,000 different molecules in some cases. He began studying them and the genetic material that codes for them. "What you have in frog skin is a whole library of molecules that are counterparts to those found in the hormonal or nervous systems of other animals, including humans," he explains. Here, then, was an opportunity - a ready-made pool of biologically active materials ripe for exploitation.

Shaw and his colleagues extract the venom by electrically stimulating the tiny muscles in the venom glands. This causes them to extrude the toxin onto the surface of the skin. It can then be washed off, recovered and freeze-dried ready for analysis.

The stimulating current - provided by the equivalent of a personal stereo battery - is small and does no harm. So, as with snakes kept in captivity for their venom, the frogs can be "milked" again and again without injury. And the technique is simple enough to use in the field.

The group has so far studied 50 species. Among the discoveries is a peptide from the giant Mexican leaf frog that can reduce blood pressure and acts as an anti-coagulant. Other peptides, from the North American pond frog, seem to influence the growth of tumours and might be useful in the treatment of cancer. As the planet is home to some 4,000 species of frog, the team has a fair way to go.

Many amphibians also produce molecules with antibiotic actions - presumably because the moist, permeable skin through which they respire leaves them vulnerable to microbial attack. Some of these antimicrobial molecules work by breaching the outer membranes of invading bacteria, a mode of action that Shaw believes should make them less subject to the weakness of most antibiotics: resistance. "The Chinese use dried frog skin in some of their traditional medicines," he says.

Frog toxins might also find a future outside medicine. African running frogs make a poison to rebuff the large insects that prey on them. With colleagues working in plant sciences, Shaw is aiming to genetically engineer a plant that expresses the gene for this venom. The plant he is focusing on is cotton.

"In the southern states of America there are some 10 million acres of cotton. It is a difficult crop to grow because it has a whole range of pests, many specific to it such as the boll weevil. To produce a crop, farmers have to spend $200 (£140) an acre on pesticides. These, in turn, damage the environment - insects, song birds and so on."

If Shaw can make a transgenic cotton plant that switches on its venom gene when an insect starts chewing, the attacker should be paralysed within minutes. And as cotton is not a food crop, there would be no fears about a threat to human health.

Several of the molecules devised by Shaw and his colleagues have been patented and he has hopes that some of them will eventually find a commercial home. He has recently returned from his latest collecting expedition: to the temperate and tropical rain forests of southern China. The search goes on.

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