IF YOU go down to the woods today you鈥檙e sure of a big surprise: the bizarre sight of grown men and women whooping with delight as they hurl blankets into the undergrowth and drag them out again. This spectacle, which can be seen from time to time in the New Forest in southern England, is not a twisted re-enactment of the teddy bears鈥� picnic but an attempt to capture ticks, the pinhead-sized parasites that feed on the blood of humans and animals.
When the tick hunters emerge from the forest, having carefully inspected themselves to ensure no ticks are making a meal of them, they extract the captured bugs鈥� salivary glands and blend them up to create a tick spit soup. The scientists, who work for the Oxford-based biotech firm Evolutec, believe this unpromising-looking grey gloop will prove a source of potent new drugs.
Researchers are not just targeting tick saliva. Others are going after leeches, hookworms, vampire bats and sandflies for the same reason. These creatures have one thing in common. They are all bloodsucking parasites, making their living from other organisms. Over millions of years they have evolved cunning ways to manipulate their hosts for their own ends. They make chemicals that prevent blood clotting, stimulate blood flow, or shield the parasites from their hosts鈥� immune defences. But with satisfying irony, humans are now starting to exploit the compounds that these parasites produce as a source of potential new medicines. A molecule that dissolves blood clots, for instance, could be a lifesaver for heart-attack patients. An immune-suppressing compound could be useful in diseases caused by an overactive immune system, such as asthma and allergies.
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The idea of 鈥渂ioprospecting鈥濃�� searching for novel drugs from plants or animals鈥� isn鈥檛 new, but according to Richard Titus, a biologist at Colorado State University, the evolutionary arms race between parasites and hosts could be one of the best hunting grounds yet. 鈥淭hat sort of co-evolution has to have produced some very interesting phenomena at the interface between bloodsucking arthropods and humans, with very potent molecules mediating the effects,鈥� he says.
The first parasite to be exploited by humans was the bloodsucking leech. Since Biblical times, doctors have practised the art of leeching, applying the creatures to patients鈥� skin to suck out what was believed to be 鈥渆xcess鈥� blood. It was a sure-fire cure for anything from gonorrhoea to hysteria, they insisted. Indeed, the creatures are used to this day to drain blood during certain types of microsurgery. The point of using leeches, rather than just opening a cut with a scalpel is that leeches can carry on supping blood long after an ordinary wound would have clotted up.
The secret is a molecule in leech saliva called hirudin. It has exactly the right shape and electrical charge to bind to the blood protein thrombin, which is a key enzyme in the clotting process. Fine-tuned by evolution, hirudin is so effective that a leech can gorge itself without the wound running dry.
The pharmaceuticals company Aventis has managed to genetically engineer bacteria to churn out hirudin, and four years ago began selling the stuff to hospitals as a blood thinner or 鈥渁nticoagulant鈥�. It is used to prevent the life-threatening blood clots that can form as a result of damage to blood vessels during surgery.
Unfortunately hirudin is no panacea. It can only be given on a few occasions in a patient鈥檚 lifetime before the immune system learns to recognise it as foreign, and fights it off with increasing numbers of antibodies each time.
But why stop with leeches? There are an estimated 40,000 different species of parasite that drink human or animal blood. 杏吧原创s have begun to wonder whether any more of them use the blood-thinning trick, perhaps with better, less 鈥渋mmunogenic鈥� anticoagulants. A complex cascade of chemical reactions controls the transformation of free-flowing blood into jelly-like clots, so there are lots of points at which different parasites could subvert the process.
Take hookworms, which live inside the gut of humans and other animals, feeding on its rich blood supply. Like leeches, they use an anticoagulant, and California-based firm Corvas has isolated the chemical, called nematode anticoagulant protein or NAPc2. It binds to factor VIIa, a blood enzyme involved at the start of the clotting cascade before thrombin gets a look-in. NAPc2 is also being investigated for use after operations, initially knee-replacement surgery. About 25 per cent of patients get blood clots in their leg after this operation. A trial last year found that if patients were injected with NAPc2 within an hour of surgery, only 12 per cent got a blood clot. The compound is also being investigated for the treatment of angina, to cut the risk of narrowed cardiac arteries becoming blocked by a blood clot and causing a heart attack.
But there are larger bloodsuckers in the bioprospectors鈥� sights. Vampire bats, which live in North and South America, feast on the blood of cattle and other large mammals. They too need a nice long drink of blood without clots getting in the way. The unusual effects of vampire bat saliva on blood were first noticed by scientists at London Zoo in the 1930s. Researchers at biotech firm Paion in Berlin have now isolated a chemical from bat spit called desmoteplase that can actually dissolve clots. There are already a few 鈥渃lot-busting鈥� drugs available, given to patients after a heart attack or stroke, but among other drawbacks they have to be injected within a few hours of the event to be effective. Paion says desmoteplase, by contrast, looks like it could be effective up to nine hours afterwards.
Meanwhile, researchers are discovering other weapons that we could turn to our advantage. Here鈥檚 where the ticks come in. Ticks are masters of the stealth attack, says Evolutec鈥檚 development director Wynne Weston-Davies. They jump onto their host鈥� usually deer or other mammals, including humans鈥� bite down and sit unnoticed while they gorge themselves on blood.
When an insect bites, the physical damage to the skin and the foreign proteins in the bug鈥檚 saliva usually trigger a localised immune reaction. Specialised skin cells called mast cells release several chemicals, including one called histamine, which signal inflammation. The skin becomes red and itchy, encouraging the human or animal to scratch and hopefully dislodge the insect. But ticks somehow prevent this reaction. 鈥淭hey can be there for 12 to 14 days without being noticed,鈥� says Weston-Davies. 鈥淲e knew they had to have something extremely clever.鈥�
In fact, it turns out ticks have numerous smart ways to stymie their hosts鈥� defences. Tick saliva contains at least 300 chemicals that affect mammals鈥� immune defences and blood system. These include histamine-binding proteins (HBPs), which latch onto histamine with a grip up to a hundred times stronger than the body鈥檚 own receptors for it. It鈥檚 the HBPs in tick saliva that mop up histamine and so block inflammation.
But histamine isn鈥檛 just behind itchy red insect bites. Diseases such as hay fever, asthma and conjunctivitis also involve an overactive inflammatory response mediated by histamine. Evolutec has been testing one of the HBPs, which it calls EV131, as a treatment for such conditions. The first trials in humans are due to start this autumn, initially for conjunctivitis. Volunteers will get EV131 eye drops in one eye and control eye drops in the other. If all goes well, it could be on the market in two years, says Weston-Davies.
One of the potential problems Evolutec scientists will be watching out for in patients is the production of antibodies to EV131. The compound has been found to trigger antibody production in mice, but these antibodies do not seem to block the critical histamine-binding site, allowing the drug to keep on working.
Weston-Davies says: 鈥淭icks pre-date the dinosaurs by a long way, so they鈥檝e had an awfully long time to get things right by natural selection, and it seems they鈥檝e selected for very low immunogenicity.鈥�
But when it comes to making drugs from creepy-crawlies鈥� spit, an immune reaction against the proteins it contains will always be a possibility after months or years of treatment. Bloodsucking creatures only need to hold off the immune system for long enough to get a square meal, after all. So scientists at Munich University have decided to go a step further. They plan to use the natural compounds as a starting point for designing synthetic chemicals that do the same job but are less immunogenic. Clinical biochemist Christian Sommerhoff says this is particularly important for chronic inflammatory diseases, for which long-term treatments are needed. 鈥淪ooner or later all foreign proteins will probably induce an allergic response,鈥� he says. 鈥淲e鈥檙e just using them as building plans.鈥�
Sommerhoff鈥檚 team has isolated an anti-inflammatory compound in leech saliva that blocks another of the chemicals released by mast cells, an enzyme called tryptase. They have worked out the exact three-dimensional shape of 鈥渓eech-derived tryptase inhibitor鈥� and are using it as a starting point for designing synthetic anti-inflammatory drugs for tackling asthma and the skin condition psoriasis.
Of course, there are times when an immune response is desirable. While studying sandfly spit, Richard Titus and his colleagues at Colorado State University at Fort Collins encountered a molecule that provokes a strong immune response, and decided to turn it to their advantage. The sandfly uses the opposite hunting strategy to the tick. Instead of feeding stealthily for as long as possible, it鈥檚 a smash-and-grab operator. It secretes a chemical that acts as a 鈥渧asodilator鈥�, causing the host鈥檚 blood vessels to widen so that extra blood is pumped to the area. Although the host will become aware of the fly鈥檚 presence within a few seconds, that鈥檚 long enough for the insect to drink its fill.
Titus and his team have isolated the chemical, called maxadilan, which they claim to be the most potent vasodilator ever discovered. They initially hoped that the compound could be used to promote blood flow after brain surgery, to prevent the normal response of shutting off blood supply to the wound. Unfortunately animal studies suggested maxadilan would trigger too strong an immune response for this use. But this gave Titus another idea.
They began testing maxadilan as a potential vaccine鈥� harnessing the immune response and making it work for them. Because while sandflies themselves cause little direct harm to humans, they often pass on the single-celled organism that causes 鈥渂lack fever鈥� (or leishmaniasis), a deadly and disfiguring disease of hot climates. Surprisingly, an immune response against maxadilan seems to prevent the black fever bug getting a toehold 鈥� at least in mice. Although the animal tests also showed that maxadilan had too strong a vasodilatory effect to be used as the vaccine itself, Titus is now investigating other chemicals in sandfly saliva instead.
Their unlikely strategy was validated last year when their colleagues at the National Institutes of Health near Washington DC, led by Jose Ribeiro, hit the headlines with proof that a sandfly saliva protein called SP15 made an effective vaccine in mice. Ribeiro鈥檚 team plans to start tests of its vaccine in Brazil, not on humans but on dogs, the principal reservoir for the sandfly. Titus, meanwhile, is also organising canine trials of their lead vaccine candidate. A dog vaccine could have a substantial impact on the rate of transmission to humans, but the researchers hope that human trials will follow.
Evolutec is using a similar approach to develop a vaccine against Lyme disease, a debilitating form of arthritis that鈥檚 transmitted by tick bites and is common in the US. In this instance, the researchers are trying to stimulate an immune response to a glue-like substance called 鈥渃ement protein鈥� that helps ticks to stick to their host. So far, the vaccine seems to work well in mice, and trials in cattle are now under way in Kenya, where ticks are a major livestock pest.
Bloodsucking parasites may have had it all their own way for millions of years, but by a twist of fate their chemical weapons are now being subverted to humans鈥� advantage in ever more creative ways. If the Evolutec researchers succeed, all those trips to the New Forest will have been worth far more than the cost of a few blankets.