THE SHEEP THAT SAVE LIVES

Scientists on a Welsh hill farm are pioneering a new way of harvesting antibodies effective against snakebite, drug overdoses, dysentery and dental plaque. Living sheep and hens provide a constant supply, in their blood and eggs

In the distance, in a fold in the hills, the white smoke of a wood fire curls lazily from a farmhouse chimney into the pink, early evening sky. Animals are grazing in the hedge-lined fields, a tractor meanders down a narrow lane returning home at the end of the day, and the sound of a distant barking dog floats up to the fields from the valley below. Nearby, in each of a dozen or so fields clustered around a huddle of barns, sheep are beginning to gather together for warmth at the start of the what has all the hallmarks of a cold spring night to come.

At first Blaen Farm looks like any of the other large sheep farms in this part of rural Wales. But big differences soon become apparent. There are no lambs among the flock of 2,000 sheep, all the animals are ewes and many are, by modern farming practices, very old. The buildings are also bigger than those of an ordinary farm, the access roads are wide, and the brightly lit office block, the electronic equipment and the car parks, all make the farm different from all its neighbours in this remote, sparsely populated area of west Wales.

Blaen Farm, tucked away in the rolling green hills, is a unique farm where the workers wear white coats and suits and are more at home with test tubes than tractors, and where the harvest is blood rather than meat. The sheep grazing here will not have lambs, and nor will they be slaughtered for Sunday roasts. The eggs soon to be laid by a new batch of chickens will never be poached, boiled, scrambled or fried.

The sheep are being bred for the contents of their blood, and the chickens will be reared for what is in the yolks of their eggs. The end products will be naturally-produced cures for such problems as snake bites, scorpion stings, and drug overdoses.

Blaen Farm is a biological factory making antibodies where the only production machines are the animals, and where a special blood transfusion room for sheep has replaced the former dairy farm's old milking parlour.

The sheep grazing here in Wales are the world's biggest producers of antidotes to snake bites and are credited with saving several hundred lives in trials in countries across the world, from Sweden to Sri Lanka. In a two-week trial in northern Nigeria, the antidotes to the deadly carpet viper generated by sheep on the farm, saved the lives of 40 people. Around the world, several hundred lives have been saved by the inexpensive, sheep- produced antidotes, from a Sri Lankan farmer to a shepherdess in northern Italy.

Not only is Blaen Farm the biggest producer with the widest range, it also makes them in an altogether different way to most of its competitors. While pharmaceutical companies around the world are spending large amount of money on developing antibodies by fusing cells taken from dead animals, Professor John Landon and his team on the farm rely on nature rather than manufacturing processes to produce antibodies for disorders from life- threatening bites and overdoses to dental plaque.

Professor Landon, founder and research chief of Therapeutic Antibodies, the company which runs the farm, says the technique he uses (producing polyclonal antibodies) is the right one, and that the manufacturing approach (making monoclonal antibodies) is in many cases over-complicated and unnecessary.

"Everybody else is too snobbish to use the old-fashioned way. The world has assumed that monoclonal antibodies are the answer and nobody seems to have asked themselves why nature always mounts a polyclonal response," he says.

Antibodies, nature's way of combating toxic invaders, are immunoglobulins - special proteins made up of amino acids - that are produced within the body to counter specific antigens, including infections, toxins, viruses, and bacteria. When any kind of infection or disease arrives, specific antibodies deal with the invasion.

A century ago, two scientists, Behing and Kitasto, conducted the investigations that took nature one step further and established that an antibody produced by one animal would also work in another. They found that serum from an immunised rabbit could neutralise the tetanus or diphtheria toxin, and that when injected into mice and guinea pigs it gave them immunity too. Another scientist, von Gehring, later used serum from horses which had been immunised with the diphtheria toxin to reduce illness and death rates among children from the disease.

In recent years, since 1975 when the first research began to be reported, the production of monoclonal antibodies (those manufactured from biological material for specific purposes) has grown significantly, particularly in the treatment of cancer. The idea here is that the antibodies target the antigen on the surface of the tumour itself and guide the required drug therapy to the cancer itself, avoiding damage to surrounding healthy tissue.

In the production of monoclonal antidotes, as practised elsewhere, the provider animal is immunised with a tiny amount of poison, infection or bacteria, then has its spleen removed. The lymphocytes (antibody-producing cells) are taken out of the spleen and mixed with myeloma cancer cells taken from the same animal. Single clones of the antibody can then be produced to demand.

In the polyclonal approach being used at Blaen Farm, the animal is also immunised with a tiny amount of the toxin. Here, however, the antibodies are produced naturally by the live animal and then extracted via the blood on a regular basis during the natural lifetime of the animal.

One of the benefits of the polyclonal approach is that it is simpler and cheaper. Dr David Theakston, of the Liverpool School of Tropical Medicine, says, "It took us five years to develop a monoclonal anti-venom for one viper toxin. Because of the number of toxins in viper venom, you would have to have a cocktail of monoclonal anti-venoms. It was too difficult, too complicated, too expensive."

While the monoclonal antibody is tailored for a specific target, the polyclonal adopts more of a scatter gun approach, shooting out a range of different antibodies to combat the infection or disease. "Polyclonal antibodies offer the advantages of several million years of natural evolutionary development and can be produced with a fraction of the effort and at a fraction of the cost of their monoclonal counterparts. They are also usually more effective," says Professor Landon.

At the farm in Wales, production is booming. Each of the sheep is immunised with the venom from one of 50 different kinds of snakes, including some from the world's deadliest, like the Nigerian carpet viper which kills an estimated 10,000 people a year, or with the poison from killer bees, spiders and scorpions. After being immunised on a monthly basis with tiny amounts of venom, the sheep start to produce a large quantity of antibodies to the toxin. Each month, a pint of blood is taken from them, and processed in a salt solution to form a poison antidote for humans.

Ian Rees, director of operations at the farm which employs 78 people, says, "By a fractionation process we take cells out of the blood, split out antibodies and then isolate those that attack the venom. At the end of the process you are left with a vial of antidote specific to a particular snake."

Professor Landon explains: "What happens with a snake bite is that the venom will contain a neurotoxin that will bind on to and block the transfer of an impulse down a nerve, effectively paralysing it. In order to do that it has to fit into a little receptor, rather like a key which fits into a lock, blocking the normal message transmission. Introducing an antibody is like putting chewing gum on to the key to stop it fitting into the lock."

The venom itself arrives at the farm in innocuous polystyrene boxes. The only clue to what is inside are the Third World addresses of the senders stamped on the labels. After months of such regular deliveries, arrivals of freeze-dried deadly venoms taken from the likes of the Thai cobra, the Australian tiger snake and the Mexican diamondback, generate as much excitement at Blaen Farm as the call of a double-glazing salesman.

In the heart of the Welsh countryside it is difficult to appreciate that such a small amount of harmless looking powder reconstitutes to a venom that can kill in minutes. "We get the venom either from the country of origin, or from the World Health Organisation centre for snake bites," says Ian Rees. "The venom is obtained by getting the snake to bite through a plastic-covered container which leaves the poison inside. It is then frozen and transported to us."

Demand for antibodies is growing all the time and the snake bite antidotes have huge potential in the Third World where thousands of people, particularly children, die each year, and keeping production costs down means more lives can be saved.

"A major problem with snake bites is that they occur in developing countries where there is a frequent lack of availability of anti-venoms. In Nigeria at present, the anti-venom stocks in hospitals are virtually zero and almost unobtainable unless the patients, their families or their villages can afford to pay high prices for the drugs. Many people are dying simply because they cannot afford the anti-venom or enough of it to have an adequate therapeutic value," says Dr Theakston.

The inexpensive, polyclonal approach has already paid off in one trial in Nigeria. "The trial went on for only two weeks because of the fighting in that area, but we believe that during that time we saved about 40 lives. That antidote came from a group of 40 sheep here, so in effect each saved a life," said Ian Rees.

There is also an increasing market for antibodies to overdoses with anti- depressant drugs, toxic shock and food poisoning and salmonella. A new development programme using chicken to produce antibodies to food poisoning and salmonella is about to start at the farm.

Again, it is based on nature and historical remedies that go back nearly 2,000 years when farmers first began to feed raw eggs to calves suffering from diarrhoea.

As Professor Landon explains, "We have had trials with the hens and we are now working our way through before starting up. The hens are immunised with the necessary toxin and they start producing antibodies which have been shown to be effective against gastroenteritis, salmonella, dental plaque and dysentery. They transfer the antibody to the eggs and we will collect it and use it in the same way as we do with the sheep. We are working on the ways in which it will be taken. It will probably be swallowed rather than injected, and work directly in the gut."

As Ian Rees points out, there is something of an irony about the hen project. After all it was chicken eggs that caused a widespread salmonella scare nearly a decade ago. That furore not only cost the poultry industry millions of sales, but it also led to Edwina Currie's fall from ministerial office. The transformation of the egg from food-poisoning villain into hero, could start a whole new debate about which came first, the egg or the salmonella. !

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