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Genes Sans Frontiers New Scientist 1 March 1997

LAST November, Leo Visser, a medical researcher in the Dutch city of Leiden, got a nasty shock. He discovered that the Swiss vaccine he had been testing on people since June was an illegal immigrant. It consisted of live cholera bacteria with the DNA that makes them deadly snipped out. Such genetically modified organisms need special approval, and an environmental impact assessment, before they can enter the European Union-to which the Dutch belong, and the Swiss do not. Visser's vaccine didn't have it. Somehow, that detail was missed by Visser, the importing company, the exporter, the manufacturer and the Dutch officials who gave Visser routine permission to run clinical trials. Visser stopped the trials, and applied for permission to bring the bacteria into the EU. It's a bit late. Visser's volunteers who took the oral vaccine last year have excreted it in their faeces. Genetically modified cholera has long since colonised Leiden's sewers and from there, the North Sea. But it was probably there already. The vaccine is sold legally in Switzerland and Canada. It probably ended up in a leaky British sewer the last time a Canadian nurse changed planes at Heathrow on her way to Rwanda. The point here is not that we are all going to die from some monstrous modified cholera. We'll probably be OK. Nor contrary to what most biotech firms would have us believe, is it that rules governing genetically modified organisms are ridiculously restrictive and should be dropped. If you believe that swapping genes around among species with no control but the market cannot possibly harm humanity's interests, you probably remember that the French said back in the 1980s that plutonium was safe enough to eat. Well, it isn't. The point is that safety checks on genetic engineering are now applied separately by separate countries. In a world of aeroplanes, free trade and creatures that swap DNA, this is total nonsense. Take the recent Euro-fuss over an insectresistant maize with a few extra genes (This Week, 15 February, p 10). The US, in its wisdom, last year decided this was safe. Farmers planted it, and about 1 per cent of the 30,000 tonnes of maize the US sent Europe last autumn was genetically modified. Before the EU had decided whether it was safe, it was piling up on European docks. So why did the US go ahead and export anyway? The Americans considered the maize safe, and as long as Europeans would buy it-and they need it to feed their cattle-the EU could not keep it out without risking a confrontation with the World Trade Organization. That's free trade.

When the European Commission finally agreed to permit the maize last December-despite serious scientific misgivings that were not answered to everyone's satisfaction-it was with more than half an eye on the bursting silos of Antwerp and Lorient, and the threat of trade war in Washington. The European Consumer Affairs Commissioner, Emma Bonino, declared herself "uneasy" with a decision taken "under economic pressure". So were Austria and Luxembourg, which refused to allow in US maize. Luxembourgers may sleep soundly knowing that in the unlikely event the maize results in genetic apocalypse, their tiny land will be safe. Which, of course it will not be. Genes are no respecter of borders. DNA is always turning up . where it is not expectedantibiotic resistance genes born in Japan reach California in days; crops pollinate weeds. Such spread may well have limits, but we do not know yet what they are. All we know is that biology can, if inclined, ignore political boundaries. So what point is there in the EU, or anyone, deciding what genetic modifications it will or will not permit when what it does not permit can simply sneak in through an administrative slip-up in Holland, a container ship from Boston or a U-bend at Heathrow? Is the answer a world regulatory body? The biotechnology industry has always said no. Ecology varies, it says: what is safe in one place may not be in another. And sovereign countries must be free to make their own decisions. But neither free trade nor biology have much use for sovereignty. And it is precisely because what is safe in one place is not safe in another, but could well tum up there once it is approved somewhere else, that we need some sort of global governance. This does not need to mean a new bureaucracy. We already have national biotechnology authorities effectively making decisions for everyone else. They could easily make those decisions public, and give scientists in other countries the chance to agree or object before anyone can put novel genetic creations on their markets-or in our sewers. Such consultation among national authorities is how the EU is meant to govern itself. It has been slow, but that is mostly because of Brussels's addiction to secrecy. it could work. it could be the only way to even try to control the great genetic experiment that is already under way.

Genetically-engineered Tobacco provides antigen for Hep-B test
New Scientist 18 Jan 97 p20.

JUST 10 leaves from a genetically engineered tobacco plant could provide enough antigen to test more than half a million people for the hepatitis-B virus (HBV), according to Japanese researchers. Because this technique is so much cheaper than current methods of production, the researchers hope that developing countries previously unable to afford HBV screening will now be able to go ahead. Doctors use HBV antigen to test for the presence of the virus in blood samples, where the antigen binds tightly to any HBV antibodies. Existing methods for producing the HBV antigen use bacteria or yeast as a growing medium. "Using E. coli or yeast means cultivating the antigen in special fermenters," says Yoichiro Watanabe, a plant biologist with the team that developed the new approach at the University of Teikyo. "But our new system doesn't require that kind of expensive equipment. All we have to do is cultivate the tobacco and crush the leaves." HBV, which causes serious liver damage, is one of the WHO's targets for global eradication by 2020. The virus has an incubation period ranging from three weeks to several years and can be passed on through blood transfusions or sexual contact before any symptoms appear. The Teikyo team, which is led by Yoshimi Okada, developed the new tobacco-based method for producing HBV antigens. They used tobacco because it has already been used extensively by genetic engineers and is well understood. The researchers took the gene for the antigen and injected it into agrobacteria, which are often used to shuttle genes into plants.

When tobacco plants were then infected with the agrobacteria, they each manufactured up to 10 micrograms of the HBV antigen. Okada estimates that enough antigen could be extracted from between eight and 10 leaves to test between 500 000 and 600 000 people. "We hope to have some intemational collaboration to help countries where HBV is common," says Watanabe. "We welcome any interest from such countries." The accuracy of HBV testing using the new antigen has been tested by a Red Cross blood centre near Tokyo, and found to be as reliable as tests using HBV antigens made in yeast. Currently, vaccines against HBV are also based on antigens produced in yeast, and Watanabe says it is theoretically possible to produce a similar vaccine from the tobacco. But instead of purifying the antigen, the Japanese research team wants to grow the antigen in edible plants such as tomato and pepper. "We hope that vaccination could then be possible by simply eating the plant," says Watanabe. The idea of producing edible vaccines is not new. Researchers in California have already used tobacco to grow an experimental vaccine against malaria (Technology, 21 January 1995, p 23).

Tomatoes with a pinch of salt New Scientsit 26 July 97

YEAST DNA is being drafted in to help commercial crops cope with salty soil '

In and agricultural regions, much of the water used for irrigation evaporates off the fields, leaving behind any minerals and salts dissolved in it. One of the most pernicious salts left behind is sodium, which retards root growth, stunting and sometimes killing crops. As much as 10 per cent of the world's 270 million hectares of irrigated land currently suffers from extreme salt build-up. Another 20 per cent is showing symptoms of salt damage, according to estimates from the UN Food and Agriculture Organization. Now molecular biologists in Spain and England are making salt-tolerant tomato, melon and barley plants, by tucking a saltregulating gene from brewer's yeast into the plants' chromosomes. Ramon Serrano, a molecular biologist at the Polytechnic University in Valencia, is using a gene called Hall that helps yeast cells survive in salty surroundings. So far he has tried the gene in tomato and melon plants. The transgenic varieties showed greatly improved salt tolerance in greenhouse tests of whole plants, as well as in laboratory tests of cells grown in culture dishes.

The Hall gene produces a protein that causes ion PUMPS in the cell walls to transport sodium out of the cell, while simultaneously prompting other channels to let potassium in. This exchange benefits many cellular enzymes, which generally require potassium but shun sodium, says Roger Leigh at the Institute of Arable Crops Research in Rothamsted, Herffordshire. "Most organisms like high potassium in their cells," he says. Leigh has placed Hall in barley, where he found that it works in a different way. Rather than pumping sodium out, the barley cells store it in an internal dustbin called a vacuole. Since plant vacuoles often OCCUpy most of the cell, Leigh says the Hall barley should still prove even more salt tolerant. Timothy Flowers, who is developing salt-tolerant rice at the University of Sussex, is sceptical about the chances of the transgenic crops flourishing in the field. Salt regulation is complex, he says, and cells that appear salt-tolerant in the lab often don't survive beyond the greenhouse. "I would like it to work, it's just that so many times I've seen people get egg on their face." Jonathan Knight

Potatoes which help one type of Diabetes New Scientist 26 July 1997

BY TINKERING with the genetic make-up of potatoes, Canadian researchers may have discovered a painless way to prevent people developing diabetes. Their genetically engineered potatoes can protect mice from the onset of a form of diabetes known as type 1. Type 1 diabetes develops when the body's immune system mistakenly attacks proteins including one called GAD on certain cells in the pancreas. These cells, called eyelet cells, produce insulin, which is essential for maintaining correct levels of sugar in the blood. Once they are destroyed, regular insulin injections are the only way to avoid serious illness.

Scientists have been looking for a way to treat the disease by stopping the immune system from killing eyelet cells. Many studies have focused on the idea of oral tolerance-that regularly eating large amounts of GAD could prevent the immune system from attacking the protein. The problem has been that it is difficult to manufacture GAD in bulk. A team of researchers led by Anthony Jevnikar of the University of Western Ontario believe they have the answer. They inserted the gene that codes for GAD into the DNA of potato plants, which grew to produce potatoes with high levels of GAD. For several months, the team fed these potatoes to mice that had been specially bred to be highly susceptible to diabetes. "These mice are a good model of what happens in type 1 diabetic people," says Jevnikar. "They have the same pancreas structure and immune response." In this month's Nature Medicine (vol 3, p 793), the team reports that only 2 of the 12 mice fed with the potatoes developed the disease, compared with 8 out of 10 untreated control mice. "Our ultimate goal is to see if this method will work in humans," says Jevnikar. "This is an important combination of two new technologies-oral tolerance and genetic self manipulation," says Marco Londei, an expert in the immunology of diabetes at the Kennedy Institute of Rheumatology in London. "If the approach does transfer into humans, I could imagine it being useful for treating children-they wouldn't know they were eating medicine." Jevnikar suggests that genetically altered plants could also be used to treat a variety of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. "I have a feeling this could be the first of many similar approaches to treating disease," he says. "Inducing oral tolerance by eating genetically engineered plants could even prevent rejection of transplanted organs." Stephen Pincock

Viral magic: Crops become biofactories

Engineered Tobacco-mosaic Virus Shows Biochemical Promise New Scientist Oct 97

VIRUSES engineered to wear an "overcoat" promise to turn ordinary plants into factories for important proteins such as antibodies, hormones and enzymes. Scientists at the Scottish Crop Research Institute (SCRI) in Invergowrie, near Dundee, are producing the proteins attached to the viruses' own protein coats. Their latest experiments have shown that the products are biologically active, even while attached to the viruses. The tests also suggest that virus-infected plants could be used to clean up contaminated land. The researchers are modifying RNA plant viruses such as tobacco mosaic virus (TMV) and potato virus X (PVX). Each virus is normally surrounded by 1500 to 2500 copies of its coat protein. The scientists have fused a genetic sequence, which encodes the "overcoat", to the virus's protein coat gene. Within 10 days of the virus infecting a plant, millions of its cells each produce up to 1 million modified virus particles. The overcoat can make up as much as 20 per cent of total plant protein. "All in a matter of weeks with nothing but sunshine and water," says Michael Wilson, deputy director of the SCRI. The viruses do slightly decrease the plants' growth, but Wilson says this effect is mild.

For some proteins, such as drugs that have to be purified before use, the protein will need to be separated from the virus particles. But for other applications, for instance when using antibodies to precipitate out contaminants from water, it may be more effective to keep them attached to the viruses as bioactive particles. The researchers vary the amount of protein that stays stuck to the virus by altering the length of an intermediate genetic sequence that joins the overcoat gene to the coat gene. When this produces a peptide 12 amino acids long, the resulting "glue" is very sticky (see Figure). With longer peptides, the overcoat becomes detached. To show that the overcoat proteins are biologically active while they are stuck to the viruses, Wilson's team engineered PVX to produce an overcoat containing the active region of an antibody to the herbicide diuron. Tobacco plants infected with the modified virus bound to more diuron than those infected with unmodified virus, and were more susceptible to its toxic effects. In another test, microscopic metal grids were coated with diuron. When sap taken from plants infected with both modified and unmodified PVX was spotted onto the grids, only the modified virus particles stuck to them. "This is the acid test," says Wilson. "Now we know that our protein is more than just scrambled eggs." "This is a potentially very useful and economical method," says Bill Cockburn, an expert on plant genetic engineering at the University of Leicester. Wilson believes that the principle behind the diuron experiment could be extended to the bioremediation of contaminated land. "You could use virus-infected plants to soak up anything," he says. The viruses TMV and PVX should only spread when adjacent plants rub against each other, says Wilson. But Cockburn notes that there is a slight risk that the viruses might change their means of transmission, perhaps by recombining genetically with other plant viruses. Oliver Tickell

Grape Vines Engineered to Resist Nematodes New Scientist 17 July 97

WINES produced from genetically engineered vines are edging closer to the dinner table. Researchers in California have given grapevines a gene from snowdrops that protects their roots from attack by nematodes. Dry Creek Laboratories, the company in Modesto, California, that developed the altered vines, also expects the gene to protect against sap-sucking insects. The Dry Creek researchers, led by Walter Viss, have given the vines a gene known as GNA from the snowdrop (Galanthus nivalis). The gene makes a protein that repels nematodes and sap-sucking insects. Dry Creek licensed the gene from the British company that discovered it, Axis Genetics of Cambridge. Axis has successfully tested the gene in potatoes and tobacco (Technology, 6 January 1996, p 18). Nematodes are a type of microscopic worm. They stunt vine roots and infect them with viruses that wither the plant. One of most damaging is the fanleaf virus, which is spread by the dagger nematode (Xiphinema index). The only existing treatment for vines infected with nematodes is fumigation with methyl bromide, but this will be banned in the US in the year 2000. Sap-sucking insects, especially aphid-like phylloxera (Daktulosphaira vitifoliae), devastate grapevines in California's Central Valley and elsewhere. According to Dry Creek, there are no existing methods to control phylloxera, so the GNA gene might prove invaluable to wine growers.

Viss and his colleagues inserted the GNA gene into grapevine rootstock, rather than the fruit-bearing scions that are grafted onto it. "Grapevine is a compound plant, and we're just working with the rootstock," says Viss. One advantage of inserting genes only into the rootstock is that they will not find their way into the fruit. This should make them more acceptable to consumers, Viss claims. "But we will work in future with the scion," he says. To insert the extra gene into vine embryos, Viss and his team used a standard gene shuttle called Agrobacterium tumefalens. The bacterium survives in the wild by inserting its own genetic material it into the roots of its plant hosts.

Genetic engineers routinely commandeer the bacterium to insert genes into plants. The researchers inserted the GNA gene into three commercially important rootstocks, called Freedom, 101-14, and Teleki. in all, 50 plants carrying the gene survived. Already, they have been exposed to nematodes in greenhouses as a prelude to tests outdoors next spring. "I can't comment on the results until we get all the data back from our nematologist," says Viss. Andrew Walker, assistant professor of viticulture and oenology in the University of California at Davis, says the technique could be important-if it works. Demonstrating that the gene is effective against pests will take years, he warns. Other researchers have also attempted to improve vines by introducing engineered genes into their rootstocks. Several have managed to "immunise" rootstocks against viruses for example, by inserting genes that manufacture viral coat proteins. For reasons that are not well understood, the coat pro teins produced in plants keep the real viruses at bay. According to Walker, the Paris-based wine producer Moat Hennessy is among several companies that have equipped rootstocks with the genes that make vines? the coat protein of the fanleaf virus. Moat has also broken new ground, says Walker, by engineering scions that produce Chardonnay grapes that can protect themselves against the virus. Moat says its projects are experimental, so it cannot comment at this stage.

Medicinal Moths Useful Drug Sources New Scientist 97

Medical moths: larvae are freeze-dried and pulped

THE larvae of moths and butterflies that plague gardeners could soon be put to work making drugs to save lives. "Instead of larvae eating your cabbages, you can make pharmaceuticals in them," says Alan Wood who heads the team at the Boyce Thompson Institute for Plant Research, at Cornell University in Ithaca, New York. The researchers infect the insects with viruses that trick them into making any protein they want. Wood and his colleague Patrick Hughes have experimented with the larvae of several moths and butterflies, including those of the monarch butterfly (Danaus plexippus), the silkworm (Bombyx mori), the gypsy moth (Lymantria dispar) and the tobacco hornworm (Manduca sexta), which has larvae the size of cigars. But the highest yield so far has come from the larvae of the cabbage looper moth (Trichoplusia ni) -the scourge of cabbage farmers around the world. Large quantities of the proteins can be made and extracted within days at a fraction of the usual cost. A single incubator, the size of a suitcase, can take up to 9000 individual larvae, churning out 25 grams of a protein in just three days. Hughes discovered that he could cram the insects into such a tiny space by giving each individual a lollipop-shaped stick, to mimic a plant stem or leaf surface. The larvae crawl down their supports to a food tray at the base of the incubator.

When they reached a certain point in their life cycle, the researchers spiked the food with a baculovirus engineered to carry the gene for making a pharmaceutical protein. These viruses only affect arthropods. The viruses carry the gene with them into every cell they infect, turning the larvae into miniature protein factories. The team freeze-dries the insects just before they succumb to the viral infection. The timing is critical -if the larvae die naturally, their bodies are flooded with enzymes that rapidly digest and destroy the key protein. Later the researchers defrost the larvae, squash them to a pulp and extract the protein by standard separation methods, such as chromatography. So far, the team has made "marker" proteins which show that the system works in principle. These include luciferase, an enzyme from fireflies which glows, and beta galactosidase, which turns blue when exposed to standard reagents. Now, the institute is working with drugs companies to test out the system d for generating proteins that have proven medical value such as insulin or human growth factor. Wood says that he expects their technique to yield 10 to 100 times as much protein per gram of insect as a comparable system based on fermenters full of insect cells that have been genetically engineered to make a protein. "We expect costs to fall tenfold as well," he says. Andy Coghlan

Virus-engineered Plants may be Hazardous New Scientist 97

RENEWED fears over the safety of plants carrying genes from viruses may lead to curbs on genetically engineered crops in the US. Moves to clamp down on altered crops come as the biotechnology giant Monsanto awaits permission to market a potato that carries a viral gene. Meanwhile Canadian research shows that the risk of wild viruses hijacking genes from engineered crops could be far higher than suspected. At a meeting in Washington DC last week, the US Department of Agriculture outlined possible restrictions aimed at reducing the risk of creating harmful new plant viruses. Crops are given viral genes to make them resistant to attack by the virus they come from, but the USDA has become increasingly concerned that that genes might be hijacked by other viruses to create new hybrids and new diseases. The USDA called the meeting to sound out opinion on the need for restrictions. These include a possible limit on the length of genetic sequences introduced into crop plants and the banning of genes that make functional proteins. The department is also worried about particularly high-risk sequences, such as those that trigger the process of viral replication. Advocates of the technology argue that there is no evidence that recombination swapping of genetic material between viruses will produce dangerous hybrid viruses. But critics believe that not enough is yet known to say what the risks of recombination are. And some of those at the meeting suggested that it might be a smoke screen. "Will this be used to make people like me feel that these issues have been addressed?" asked Jane Rissler of the Union of Concerned Scientists. There is, however, evidence that existing viruses may pick up a trait from a transgenic plant. Some viruses seem to be recent products of recombination that arose naturally. And in laboratory experiments, viruses from which a genetic sequence has been removed have reacquired it from transgenic plants carrying the missing genes. Traits such as the ability to move more efficiently from cell to cell or to infect other kinds of plants could prove dangerous if transferred to another virus. The technology's proponents claim that if recombination were likely, new hybrid viruses would be turning up all the time. "You can go to a potato field or a tomato field, or corn or wheat, where all these viruses are living together. You don't get new viruses jumping out of these fields infecting dogs and small children," says Chuck Niblett, a plant virologist at the University of Florida in Gainesville. But Allen Miller, a plant virologist at Iowa State University, points out that transgenic plants will contain the viral genes in all their cells all the time, increasing the risk of recombination. "It's really hard to predict what's going to happen if you have a million acres all expressing a viral gene," he says. The risks may be much higher than biotechnology companies want to admit. D'Ann Rochon, a plant virologist with Agriculture Canada, described how she infected plants with a Q' cucumber mosaic virus that lacked the gene to .'2 make a protein that allows it to move from cell to cell, and then took an equivalent gene from another virus and inserted that into the :z plants. She found that there were properly functioning mosaic viruses in one in eight of the plants-which must have arisen through recombination. "Within 10 days you get a virus which is very, very fit," says Rochon. This appears to be the first time anyone has shown r-ecombination between two different kinds of viruses within a plant. Only two weeks ago, Monsanto applied for a permit to market the transgenic potato it calls Newleaf, which carries the replicase gene from the potato leaf roll virus. Replicase is responsible for making copies of viral genes. With a plant's cells awash with such genes, says Miller, recombination would be even more likely. Kurt Kleiner, Washington DC

Insect Resistant Plants could harm Insect Helpers New Scientist 16 Aug 97

PLANTS that have been genetically engineered to ward off destructive insects could also harm beneficial ones such as bees, shortening their lives and impairing their ability to recognise flower smells, researchers have found. Minh-Hsa Pham-Delugue of the Laboratory of Comparative Invertebrate Neurobiology in Bures-sur-Yvette, France, and colleagues in Britain and Belgium have investigated the effects of engineered rapeseed on pollinating insects. The rapeseed contains genes, found naturally in some plants, that produce protease inhibitorsproteins that interfere with enzymes in the intestinal tracts of insects. The idea is that beetles and other pests feeding on the leaves and stalks of the engineered rapeseed should develop a lethal case of indigestion. But bees would also be exposed to the destructive proteins, through nectar and pollen. "Rapeseed is particularly important to bees," says Pham-Delugue. "The plants do not depend strictly on bees to pollinate them, but it is the first plant to bloom in large quantities in the spring. Bees harvest a lot of nectar from them." The researchers found no protease inhibitors in the pollen or nectar of the rapeseed. But they suspect that because the proteins are expressed in the leaves and stem of the plant throughout its life, they could be present in the pollen and nectar at levels too low to be detected. If so, they could eventually become concentrated in honey stored back at the hive, which the bees feed on. To find out how bees might be affected by high levels of protease inhibitors in stored nectar, the researchers exposed captive bees to sugar solutions containing up to 100 times the concentration of proteins found in the tissues of the engineered rapeseed. Bees fed on this solution for 3 months died up to 15 days earlier than those fed on normal sugar. After 15 days, the bees had trouble learning to distinguish between the smells of flowers. The researchers are now studying whether the toxic proteins do build up in hives of bees feeding on the concentrated sugar solutions and on the transgenic plants themselves, and if so, how quickly they accumulate. They point out that the engineered rapeseed that eventually appears in farmers' fields could secrete higher levels of protease inhibitors than the plants they tested. Their work is part of a three-year project begun last October to evaluate the impact of transgenic plants on pollinating insects. Charlene Crabb

Green Light in US for Cross-species Transplants New Scientist 27 July 96

The Institute of Medicine report recommends hospitals and universities in the US should be able to transplant organs from animals to humans without federal government approval for each operation. Like the British Nuffield Council on Bioethics (NS 9 Mar 96) , the IOM concludes the risk of transmitting diseases to humans can be iminimised by carefully screening animal donors and closely monitoring human recipients. Baboon transplants have already taken place. The Nuffield group argued primates are unacceptable because they are more likely to harbour human-infectious pathogens. The IOM report does not rule out primates but stresses pigs.

Transplant Worries New Scientist 1 Mar 97 Phyllida Brown

AMERICA's health officials are under attack for allowing animal organs to be transplanted into humans, despite mounting evidence that they may bring viruses with them. The criticism comes after two teams of researchers found that pigs-the most promising source of organs for transplantcarry a virus that can infect human cells. Although the researchers have told the US Food and Drug Administration of their concerns, the FDA continues to allow transplants to take place. in the current issue of Nature Medicine (vol 3, p 282), Robin Weiss and his colleagues at the Institute of Cancer Research in London show that a retrovirus-the group of viruses that includes HIV-infects human cells in the lab. Because the virus is incorporated into the pig's DNA, it cannot be removed except by selecting genetic variants of pigs that lack the virus, and breeding them to create a virus-free strain. Weiss first revealed his team's results last year at a meeting in New York. Now David Onions, a virologist at the University of Glasgow says he has "very, very similar" results. "We think this is a matter of concern," says Onions, who advises Imutran, a British biotechnology company that is developing xenotransplant technology. "If the virus gets into human cells at all one has to take it very seriously." Last September, the FDA and the Centers for Disease Control in Atlanta published guidelines for the use of animal organs in human transplants. They recommend that animals are screened for disease, that samples of tissue should be archived, that local review boards assess the risk of infectious disease, and that people who are given organs are monitored afterwards. But Jon Allan, a virologist at the Southwest Foundation for Biomedical Research in San Antonio, Texas, has attacked the guidelines. Writing in Nature Medicine, Allan says they are "dubious" because they do not say what sort of infections should be monitored for, and because they leave the responsibility for policing transplants to surgeons and local review boards. "I think banning transplants is the least they [the FDA] can do," Allan told New Scientist. Weiss says he told the FDA about his findings last October. Weiss also wrote to the FDA in December. However, the FDA and the CDC have not changed the draft guidelines. "I think perhaps they have not thought quite deeply enough about it," says Weiss. He adds that researchers have known for 20 years that built-in, or endogenous, retroviruses that are harmless in their natural host can jump species and cause disease in their new hosts. Philip Noguchi, director of the division of cellular and gene therapies at the FDA, says that he is not surprised by the findings, which have been confirmed by the FDKs own researchers. The FDA has never iinph.ed that animal organs are safe, he says, and it issued the guidelines in draft form to stimulate discussion. Noguchi says that the FDA may now consider the need for specific tests for endogenous retroviruses in animals that are being used to provide organs for transplant. It may also take a formal role in overseeing local review boards. Pig tissues have already been transplanted into people. And alongside Weiss's results in Nature Medicine, a team that includes researchers from the biotechnology company Diacrin in Charlestovvn, Massachusetts, reports transplanting cells from the brains of pig fetuses into a patient with Parkinson's disease.

Pig Cell Transplants may help high-Cholesterol Sufferers -
New Scientist 18 Jan 1997

PEOPLE at risk of an early death from heart attacks brought on by very high inherited cholesterol levels could one day be treated with cells transplanted from pigs' livers. According to American researchers, the pig cells would clear much of the clotforming lipid from the blood. Familial hypercholesterolaemia is an inherited disease that leaves people unable to remove the LDL (low density lipoprotein) form of cholesterol from their blood. The liver cells of people with this condition lack the receptors that would normally scavenge the fatty substance from their bloodstreams. People with one faulty LDL receptor gene (heterozygotes) tend to have two to three times the normal level of cholesterol in their blood. When both LDL receptor genes are faulty, cholesterol levels are between 5 and 10 times as high as in normal people. In people with this severe form, heart attacks before the age of 20 are common. Cholesterol-lowering drugs do them little good because their serum cholesterol is so high that even a substantial reduction does not bring it down to within the normal range. The main treatment available is liver transplantation. But this is a drastic step to have to take, and there is also a serious shortage of organs for transplant. A team led by Albert Edge of the biotechnology firm Diacrin in Charlestown, Massachusetts, decided to test whether transplants of liver cells from another species could help instead. "The main advantage of xenotransplantation would be that it gets around the shortage of donated livers-and that's a very real problem," says Edge. The team tested the idea on rabbits that were suffering from a condition similar to familial hypercholesterolaemia. Using the immunosuppressant drug cyclosporin to prevent rejection, they introduced pig liver cells into the rabbits' livers (Nature Medicine, vol 3, p 48). These cells became incorporated into the rabbits' livers, providing them with functional LDL receptors that lowered cholesterol in the animals' blood by between 30 and 60 per cent for over 100 days. "We didn't expect it to be this effective," Edge told New Scientist. The researchers were particularly surprised that the single drug, cyclosporin, prevented rejection of the foreign tissue so effectively. Transplant patients usually have to be given a cocktail of drugs. Some immunologists believe the liver may be "immunologically privileged". They think the lining of blood vessels in the liver may protect liver cells from attack by antibodies. Another possibility is that liver tissue is intrinsically immunosuppressive. Edge predicts that if pig-liver cell transplants become possible in people, they will be used in patients with the less severe form of the disease-which involves only one faulty copy of the gene-who are not able to tolerate drug therapy. For people with the more severe form, even reductions in cholesterol of between 30 and 60 per cent would not be enough to improve their prospects. The continuing need to take immunosuppressant drugs could also be a problem. "Long-term cyclosporin use would be a potential concern," says Jeffrey Platt, head of surgery, paediatrics and rs' immunology at Duke University, North Carolina. People who take such drugs for long periods are more vulnerable to infection and some cancers. However, Platt says several groups are working on methods of inducing host tissue to accept transplants permanently, without the need for indefinite drug use.

New Scientist 4 Jan1997