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NS 1 dec 2001

Brave new medicine Creating human clones for no good reason is wrong

UNTIL this week its most famous creations were the typewriter and shredded wheat. Now the city of Worcester, Massachusetts, is earning a reputation for cloning human embryos (see p 4).

Most reactions to the news were utterly predictable. Bang on cue, advocates of therapeutic cloning spoke passionately about the need to continue such research to cure life-threatening illnesses, pro-life groups just as passionately about the need to stop lt in its tracks. And caught in the middle were the politicians, trying as ever to keep pace with developments in the labs and read the public's mood. And failing.

New Scientist went to press with the British government still pushing through emergency legislation designed to make it a criminal offence to implant cloned human embryos. Few dispute the need to slam this door shut. But at the same time British ministers are keener than ever to keep the door wide open on human cloning for therapeutic purposes. This is far more contentious and is what separates Britain from the rest of Europe and the US. Take the US House of Representatives. lt has already voted to make any form of human cloning a criminal offence punishable by $1 million fine and up to 10 years in prison. The only reason this law is not now being used to charge the scientists who created the clones in the news is that the Senate has not yet debated the issue. When it does, it too is likely to vote to ban all forms of human cloning-and there will be no more Worcester clones.

On the face of it, the American approach seems backward and Britain's enlightened. In fact both have problems. Ministers in Britain have too easily swallowed the line that cloning human embryos is essential to medical progress. lt is not. True, in the aftermath of Dolly, therapeutic cloning was seen as the way forward. That's why the biotech industry and so many influential scientists pushed hard to get governments to accept it. In Britain they did their job too well. Like stuck records, ministers and policy makers continue to enthuse about therapeutic cloning even though the majority of bench scientists no longer think it's possible or practicable to treat patients with cells derived from cloned embryos. They have already moved on to investigating the alternatives. Which raises an obvious question. If cloned embryos are not the key to a brave new medicine, why should we let scientists create them? Certainly the embryos in the news have revealed little of scientific value and won't cure anyone. Creating them now when there are so many unanswered questions about ordinary embryonic stem cells is hard to just@. That may change, so a blanket ban would be unwise. But we should at least insist scientists justify their research stringently beforehand to regulators armed with the will to veto all but the most necessary experiments. At present the threshold is either non-existent, set too low, or about to be set sky high. To say that a cloned ball of cells no bigger than a pinprick cannot be created to allow a grown person to live is cruelly dogmatic.

But to let scientists create as many as they want for no good purpose is just as wrong.

Don't expect any miracles

Far from heralding an age of wonder cures, cloned human embryos may be a dead end

IT HAPPENED in a quiet lab in New England. In the early hours of 10 October, Jose Cibelli took a batch of human eggs, sucked out their DNA with a pipette, and replaced it with DNA from an adult human being. Three days later, a few of the embryos the Argentinian-born scientist created were still alive. Thus was born the media frenzy about the "first human clones" that raged earlier this week. The embryos in question were mere pinpricks-no arms, no legs, just bundles of up to six cells. Yet this was what some had hoped for and others dreaded ever since Dolly the sheep was born in 1997. Whether they really are the first cloned human embryos isn't clear. South Korean researchers claimed to have created a cloned embryo in 1998, and maverick would-be cloners such as Clonaid, a company set up by the Raelian cult, also claim to have carried out experiments. But th@ company behind the latest work, Advanced Cell Technology of Worcester, Massachusetts, is the first to publish a scientific paper on cloned human embryos (online in T7ze foumal ofregenerative Medicine). What's certain is that the announcement couldn't have come at a more delicate moment for politicians. The US seems poised to bring in legislation that would ban all forms of human cloning. That left ACT no choice but to rush out the paper and launch a PR offensive. The company stresses that its research is not about cloning people but tackling the ravages of disease and old age. The embryos it has cloned are the dawn of a new era in medicine in which people with Parkinson's, diabetes and a multitude of other diseases will be patched up with spare-part tissues, ACT says. Cells from these patients will be used to create cloned embryos to supply embryonic stem cells. These will be grown into all manner of replacement tissues, all perfect matches for the patient. Tissue rejection will become a problem of the past. It was a bold pitch that inevitably drew swift criticism from religious groups and politicians. Within hours, pro-life groups were talking about power-hungry cloners crossing moral Rubicons, George W. Bush was quoted as being " 100 per cent opposed to any type of human cloning", and there were fears that ACT's research would lead to full reproductive cloning.

So who's right? Are Cibelli's embryos a recipe for miracle cures, or a disastrous step towards reproductive cloning that should be banned as soon as possible?

The surprise consensus among scientists is that they are neither. Nobody doubts ACT is indeed hoping to transform medicine. But the company's "breakthrough" comes just as other scientists are abandoning the idea of ever using cloned human embryos in the fight against disease. For months now, many have been saying that even if they can get therapeutic cloning to work, the technique would be hopelessly impractical and expensive.

Nothing ACT has done has changed this. In fact, just the opposite. Far from confirming that therapeutic cloning is feasible, most scientists thinks the creation of the first cloned human embryos shows just how nightmarishly difficult it would be.

To create the embryos (see below), Cibelli had to use 71 eggs donated by seven volunteers and carried out three failed rounds of experiments before he generated his first cloned embryo. And even the fourth, "successful" round of experiments was far from efficient.

'My fear Is the Congress will now slap a ban on this todmology before we even know it's feasible'

In it, Cibelli took nuclei from skin cells, or from the cumulus cells that surround growing eggs, and injected them into 19 denucleated eggs, only three of which began to grow. One cloned embryo divided just once, to form a two-cell bundle. Another divided twice, to form a four-cell bundle, and the third embryo split again to form a six-cell clump. After that it too failed to grow.

To be a viable source of stem cells, a human embryo would have to develop to the blastocyst stage-a mass of around 100 cells. None of the embryos got anywhere near that stage. "It's disappointing," says Harry Griffin of the Roslin Institute, which created Dolly. "Their failure to create blastocysts and derive stem cells raises questions about the value of their work."

Indeed, some think the scientists were crazy to publish before they had grown embryos to the blastocyst stage. "My fear is that this tiny step will inflame the conservatives in Congress into slapping a ban on this technology before we even know it's feasible " says Tom Okarma, the chief executive of Geron, another "stem cell" company in Menlo Park, Califomia. Worse, according to Ian Wilmut, the creator of Dolly, the embryos were so tiny they reveal almost nothing about the prospects of human clones developing further in future experiments. Embryos cruise "on autopilot" through the first two or three cell divisions, he says. Only then does the embryo's genetic material start to influence its development. Despite this, ACT insists its work is a "milestone". In 11 of the 19 cloned human embryos, it says, chromosomes took on the form only normally seen in a fertilised egg-a vital sign, the company claims, that human adult cells can be "reprogrammed' to become embryos again.

But even if researchers did manage to grow cloned human embryos to the all-important blastocyst stage, many doubt it will make any difference. Cloning is dead in the water because it requires an unfeasibly large number of eggs, says Alan Trounson, whose team at Monash University in Melbourne first extracted stem cells from cloned mouse embryos. Even though scientists have been working with mouse embryonic stem cells for years, they still need to create scores of embryos to generate a single line of usable cells. In humans this would be unworkable and unaffordable, says Trounson. In Britain alone, there are 120,000 patients with Parkinson's disease and 200,000 with juvenile diabetes. You'd need anything up to 30 million eggs to treat them all with therapeutic cloning. Yet a woman cannot donate more than a dozen eggs a month-and this is an unpleasant and sometimes risky procedure, involving daily injections of powerful hormones followed by surgery. ACT got its egg donors by advertising in local newspapers and offering payments of $4000, the same amount given to women who donate eggs for infertility treatments. What's more, it takes so long to generate stem cells that many patients with serious diseases would die long before any of their cloned tissue was ready for implanting. Working with ordinary human embryos, teams at the University of Wisconsin and at Johns Hopkins University spent years generating just two viable supplies of human embryonic stem cells. Repeating this process for individual patients using the much trickier process of cloning embryos simply isn't realistic. "Therapeutic cloning is not going to be a practical technique," says Griffin. This is why many teams are now abandoning work on therapeutic cloning in favour of alternative ways of making compatible tissues for spare-part surgery. Trounson's team is focusing on two approaches that make eggs redundant. One idea is to identify the chemical cues in eggs that tell adult cells to turn back into embryos. Armed with these substances, scientists could in theory turn any cell into an embryo without needing an egg.

Another possibility is to take adult body cells and fuse them with embryonic stem cells. Earlier this year scientists at PPL Therapeutics at the Roslin Institute claimed to have used such an approach to turn skin cells back into stem cells and then into heart muscle cells. Even Geron, ACT's bitter rival and onetime staunch advocate of therapeutic cloning, has moved on. It is armed with its own supplies of non-cloned human embryonic stem cells and says it has successfully converted them into heart, nerve and liver cells. It hopes that stocks of these cells can provide "off-the-peg" tissue suitable for many patients. To overcome immune rejection, Geron intends to engineer the cells so that they become immunologically "silent". It hopes to insert viral genes into the cell to disable the proteosome, which generates the protein fragments on a cell's surface that make the cell and its contents visible to the immune system. "If we can interrupt that throughout differentiation, we've got the problem licked," says Okarma.

The problem with these alternatives to therapeutic cloning is that it's hard to know how seriously to take them. Citing commercial confidentiality, neither Geron nor PPL Therapeutics, two of the key players, have published any details, leaving other researchers in the dark. And nothing on the horizon suggests these companies are about to become more open about their stem cell work.

Unlike ACT. The company's claims may have been criticised as premature and their rush to print as hasty. But on one front they cannot be faulted: at least they published their findings. Andy Coghlan, Claire Ainsworth and David Concar

In addition to creating cloned embryos, Advanced Celi Technology also created human embryos through parthenogenesis, the process that leads to "virgin births" in some reptiles, birds and insects.

In parthenogenesis, an unfertilised egg ~ develops as if fertilised. In mammals, this sometimes occurs accidentally but the resulting embryos either die or turn into ovarian tumours. It's precisely becaus parthenogenic embryos don't have the potential to become human that American companies like ACT are interested in them.

They hope the technique wili escape a forthcoming US ban on all human cloning. ACT's researchers exposed 22 human eggs to chemicals that kick-start parthenogenesis. After two days, 20 of the resulting embryos had reached the four-celI P5 stage. By five days, six had developed into a ball of cells resembling an early embryonic stage known as a blastocyst.

"These are exciting preliminary results," says Bob Lanza, vice-president of medical and scientific development at ACT. .

But none of the six embryos developed an inner cell mass, the part of a blastocyst that develops into the body, rather than the placenta, and from which stem cells are taken, according to the paper published by ACT. A patent application seen by New Scientist (6 October, p 14), however, suggests that the company has gone much further with monkey cells, managing to both extract parthenogenic stem cells and get them to specialise. The company hopes tissues grown from human parthenogenic stem cells could be used for implantation. A woman couid donate her own eggs for this purpose. The resulting stem cells wouldn't be geneticaily identical to her own cells, as they contain two duplicated sets of chromosomes instead of two different sets, but tissues grown from them should not cause any problems with rejeration. For men, things would be trickier, but it might be possible to create an embryo by injecting two nuciei from sperm into a denucleated egg. But ACT has yet to prove that stem cells can be derived from human parthenogenic embryos, let alone whether tissues made from them will be safe to implant into people. Michael Le Page

A QuestIon of trust NS US and the bio warfare treaty 1 dec 2001

IN GENEVA this week, countries that ban germ warfare are wondering whether they should even bother to keep meeting. Their doubts follow the final rejection by the US of a protocol designed to boost compliance with the Biological Weapons Convention (see p 11).

Under this package of measures, countries would exchange information about biological research and quickly send inspection teams to suspicious disease outbreaks. The US claims this won't catch cheaters but, rather, give them a respectable face to hide behind.

This may be so. But nobody ever said the protocol would guarantee compliance, just that it would make cheating harder-partly by making nations develop and share technologies and expertise for detecting the cheats. The Bush administration Is opposed to multilateral arms controls because it expects others to cheat, and because it does not want foreign inspectors on its own territory. The US delegation in Geneva said that countries should simply trust it when it says it complies with the biological weapons treaty. Meanwhile, the other treaty members should certainly keep meeting, and go ahead with as many of the protocol measures as is possible without the US. At least this will tell countries that wavered about the protocol-Iran, China and the rest-that others are watching. And it wilf remind the US that trust has to be earned.

Bioweapons treaty withers

THE future of biological weapons control hangs in the balance

As Now Scientist went to press, 144 signatories to the 1972 Biological Weapons Convention were debating in Geneva whether there any point in having further discussions. Since 1980, there have of meetings to review the convention to discuss ways of enforcing it. But earlier this year, the US rejected a treaty protocol that set out various enforcement measures. The draft protocol that was under negotiation for the past seven years is dead, and it Is not going to be resurrected,' John Bolton, the American undemecretary of state fbr arms control, said in Geneva. Her repeated the measures the us governments to adopt instead (New Scientist, 10 November, p 5), most of which have been cherry-picked from the rejected protocol One requires treaty members to together.

No one Is calling for the treaty to be abolished. But if members take no joint action to police or strengthen the treaty, some delegates fear intemational efforts to control bioweapons will wither. In Geneva, the European Union was calling for members to at least agree to meet annually, which the treaty does not now require.

The EU also wants members to agree to mandatory exchanges of information about biological research and manufacturing, as knowing about legitimate uses of biotechnology makes it easier to spot wrongdoers.

Industrialised members are already supposed to do this voluntarily, but the Us largely has not. it seems likely to veto mandatory exchanges.

NS 15 dec 2001

One cell to heal them all No matter who you are, your body won't reject this univemal healer

THERE'S a type of stem cell that does not trigger rejection, even in transplants from one species to another, researchers have discovered. That means stem cells from a donor could be transplanted into anyone else, for example to regrow bone, replace cartilage or repair damaged hearts.

The finding comes as a surprise. "It does go against our common understanding of the immune system,' says Annemarie Moseley, chief executive of Osiris Therapeutics in Baltimore, a company working on the "mesenchymal stem cells' (MSCs).

Preventing the immune system attacking implanted stem cells is a massive problem. Stem cells derived from cloned embryos would be genetically identical to the donor, which is why companies like Advanced Cell Technology are working on therapeutic cloning (see p 14). Others are trying to engineer stem cells that lack the genes for the cell surface proteins the immune system recognises and attacks. But all this work may be unnecessary. Studies at Osiris and the Dana Farber Cancer Institute in Boston have shown that MSCs from the bone marrow of adults do not carry the markers on their surface that lead to rejection. And that's still true even after the cells differentiate into specialised tissues such as bone or fat, says Moseley. In fact, the cells are so good at evading rejection that transplanting them from pigs to rats does not trigger a response, according to unpublished work by Ray Chin of McGill University in Montreal. Osiris has already given around 100 people MSCs donated by their family members, some of whom were poor matches. Some of the cells were given to cancer patients to replace bone marrow destroyed by treatment. Others are being used to regenerate bone in the jaw. Up to four years later, says Moseley, the transplants haven't been rejected. What's more, Chin has shown that MSCs injected into rats quickly home in on the bone marrow. But within hours of a heart injury, the MSCs get into the bloodstream, and can later be found in the rat's hearts. The cells seem to go only to damaged areas, Chill says. 'They turned into heart muscle, blood vessels and fibrous tissue.' Osiris has found very similar results in pig studies. Clinical trials to test the same approach in patients who have suffered heart injury are being worked out with the FDA and are due to begin next year, says Moseley.

Research so far suggests that hospitals could keep pools of MSCs ready to transplant into people who've had heart attacks, for example, where they'd leap into action to repair the damage. We already have reserves of our own MSCS, but their numbers fall dramatically as we age. Getting hold of the cells should be relatively easy. MSCs don't grow indefinitely in culture, but enough can be grown from a single bone marrow donation to treat 10, 000 people or more.

If MSCs live up to their promise, there may be little need for embryonic stem cells. But it's not yet clear if they are as versatile. So far, MSCs have only been shown to give rise to about six kinds of tissue, including bone, cartilage, tendon and muscle. But mouse studies suggest their potential may be greater, perhaps even including neural cells.

Some studies also show that MSCs do not turn into cancerous masses when transplanted, as sometimes happens with embryonic stem cells. But even if MSCs prove their worth in clinical trials, research with embryonic stem cells should not be considered irrelevant, says Diane Krause of Yale University.

There might be many types of tissue that MSCs will not be able to repair, says Krause. 'It would be wrong to conclude that research with embryonic stem cells should stop.' Sylvia Pagin Westphat Boston

Death knell sounds for nuclear energy

Leaked British government report sets out a nuclear-free future

NUCLEAR power may have had its day. The best way to cut carbon pollution and tackle global warming is to replace oil and coalfired power stations with renewable energy sources, says a draft British government review leaked to New Scientist. Nuclear power is simply too dangerous and expensive. The review attempts to lay out Britain's energy strategy for the next 50 years. If the government accepts its recommendations, Britain will become one of the most environmentally friendly energy producers in the world.

The long-awaited study had been widely expected to embrace the nuclear industry's plans for up to 15 new nuclear stations. Instead, it relegates nuclear power to an alsoran that could be totally phased out by 2050 if renewable sources deliver as expected.

This happens under both main scenarios put forward in the study. One, labelled "global sustainability", assumes government intervention by regulation and financial incentives, leading to a 30 per cent contribution from renewables and a 60 per cent cut in carbon emissions. The alternative .world markets" scenario envisages a big rise in oil and gas consumption driven by consumer demand, resulting in a 20 per cent increase in carbon pollution (see Chart). Public fears about nuclear safety seem to have influenced the review, which was undertaken by the Cabinet's Performance and Innovation Unit (PIU). The technology has "an uncertain role", the report says, "since concerns about radioactive waste accidents, terrorism and proliferation may limit or preclude its use". It also wants the cost of insuring against accidents and disposing of radioactive waste to be borne by nuclear stations rather than the government.

This makes nuclear power very expensive. It is estimated that it will cost 3.0 to 4.5 pence per kilowatt-hour by 2020, compared with 1.5 to 2.4 p/kWh for onshore wind power. Combined heat and power comes in at 1.6 to 2.4 p/kWh and gas-fired generation at 1.8 to 2.1 p/kWh. 'Nowhere in the world have new nuclear stations yet been financed within a liberalised electricity market,' the report points out.

The report is enthusiastic about the potential of renewable energy, which it says is the most flexible way to reduce carbon emissions. It suggests producing at least 20 per cent of electricity from renewable sources by 2020, compared with the current target of 10 per cent by 2010. That could be achieved by massively expanding the number of wind turbines on land and offshore, and by introducing wave power and underwater tidal generators.

This is backed by another government study published this week, suggesting that Scotland on its own could produce 60 gigawatts of renewable power, three-quarters of Britain's installed generating capacity.

It also urges the government to encourage the development of combined heat and power, which uses the heat from electricity generation rather than wasting it, and to set a target for a 20 per cent improvement in domestic energy efficiency by 2010.

The report will be a bitter disappointment to the nuclear industry, which had been expecting it to kick-start a nuclear renaissance. But it does urge the government to contribute to international efforts to design cheaper, safer reactors, and to ensure that Britain's nuclear regulators are 'adequately staffed" to assess them. Nick Goodall, chief executive of the British Wind Energy Association says he is delighted by the report. But Malcolm Grimston, a senior research fellow at the Royal Institute of International Affairs in London, who used to work in the nuclear industry, warns that it might be too optimistic about the.prospects for renewablesjust as the nuclear industry was about its technology 30 years ago. Rob Edwards

Squeaky clean Nuclear power just doesn't make the grade

THE spectre of catastrophic climate change is forcing nations around the world to question how they make their energy. With carbon dioxide pushing up the global temperature, most governments agree that they must move away from the Victorian technologies of burning coal and oil towards cleaner options. But which ones?

Logically, one solution should be nuclear power because it emits no carbon. That's certainly what the nuclear industry argues, and it is one reason why countries such as China, Japan and the US, are contemplating building more nuclear power stations. That logic, however, is flawed, argues the British government's energy review, the latest draft of which was leaked to New Scientist this week (see p 5). This independent assessment shows that the cost assumptions of the past were over-optimistic: nuclear power is relatively expensive. To rub salt in the wound, it says nuclear power is feared by the public and burdened with the 'unsolved problem" of radioactive waste. What's more, the nuclear industry's future building plans are 'large and relatively inflexible", it says.

Instead, the review argues that a combination of renewable energy schemes and improved energy efficiency would be beitter, cheaper and offer more security. lt would mean building thousands of new wind turbines, first on land then at sea, followed by wave machines and underwater tidal generators.

Biomass plants would help to smooth out the peaks and troughs of these intermittent sources. The review envisions a more complex, flexible system hooking together hundreds of small generators. lt is, the review says, "a radical agenda" which would send Britain in a totally new direction.

To make all this happen will take some serious rethinking. lt would need investment in research and development to bring on nascent technologies and a range of incentives to encourage companies to build energy farms. The kind of dramatic leap in energy efficiency the review proposes would also mean creating new incentives. Conserving energy is a worthy goal, but it's just not "sexy" and often means large injections of cash. Still, the review concludes that even in the home-where lots of energy is wasted-it wouldn't take much money to make large savings.

The review's proposals undoubtedly carry serious repercussions. The biggest casualty would be the nuclear power industry, which would wind down in the coming decades. The coal industry would disappear-though it's been living on borrowed time for years. The oil industry would also take a beating, though it has fast been giving itself a green makeover by investing in renewable energy technologies.

The review paints a picture of an energy policy that could set an example to the world. When it is delivered to Prime Minister Tony Blair later this month, he should seize the opportunity with both hands. lt is the nearest thing yet to his cherished notion of the "green industrial revolution".

Huge chunk of our genome is set to be privatised

AS MUCH as an eighth of the human genome could be patented in one go. Last week British company Oxford GlycoSciences announced that it had filed for patents on 4000 human proteins and the genes that code for them. They're all proteins linked with illness, spotted by comparing healthy and diseased tissue. "We think it's the biggest group of disease-specific proteins anyone's ever filed for," says Michael Kranda, chief executive officer at OGS. The entire human genome only contains an estimated 30,000 genes. Opponents of gene patenting are appalled. "It's pretty shocking," says Helen Wallace of the British lobby group GeneWatch. "It's another stop in the selfish, immoral race to own human genes," she says. Kranda rejects this. He says that the company's application breaks no new ground. "These are the same kind of patents everyone's filed for the past ten years," he says. But Wallace says the patents will discourage other teams from doing research on these proteins. "it means that other companies and research institutes can't develop treatments based on the same genes without being challenged by OGS," she says.

And OGS plans to guard its "crown jewels" jealously. If anyone develops drugs based on the patented proteins without permission, the company intends to pursue them for royalties. "Our goal is to keep ownership," says Kranda. "We'll be happy to license some targets to those who want to spend money pursuing them," he adds.

OGS made its discoveries by meticulously comparing the proteins churned out by healthy and diseased tissue. The company has discovered many markers or antigens that are unique to diseased tissue such as cancers. Through exclusive collaborations with other companies, OGS hopes to develop antibodies and drugs that attack and destroy diseased tissue by homing in on these antigens or other distinctive proteins. "Our goal is to develop drugs," Kranda says. The company's priorities are breast cancer and various blood and lymph cancers. But it has also identified rogue proteins linked to neurological disorders and fungal infections. Andy Coghtan

Genetic roulette A small problem for a man can become a disaster for his children

A POPULAR IVF technique may increase the risk of babies being born with abnormalities such as ambiguous genitalia.

For roughly 5 per cent of men seeking fertility treatment because they have few or no sperm, the cause is a tiny mutation in the Y chromosome called a microdeletion. As long as the man still produces a few sperm, however, it is sometimes possible to inject one directly into the egg-a technique called intracytoplasmic sperm injection.

One of the reasons ICSI is controversial is that if there's a genetic reason for the k man's infertility, it will be passed on to his sons. Many couples are prepared to use ICSI anyway, arguing that it will also be available to their children.

But evidence presented at a symposium at the Monash Institute of Reproduction and Development in Melbourne last week suggests that microdeletions on the Y chromosome are a precursor to more serious genetic faults. Ken McElreavey of the Pasteur Institute in Paris found that in eight men with microdeletions, Y chromosomes were missing in about 10 per cent of the cells in their bodies. In the three who had enough sperm to test, up to 18 per cent of the sperm lacked a Y chromosome.

'The loss of the Y chromosome in some of a baby's cells can cause either ambiguous genitalia or Turner's syndrome, or both'

These findings suggest that the microdeletion is a sign of a chromosomal instability that causes some cells to lose the entire Y chromosome, McElreavey says. The loss of the Y chromosome in some of a baby's cells-called genetic mosaicismcan cause either ambiguous genitalia or Turner's syndrome, or both. Women with Turner's have normal female genitals, but they are unusually short and do not go through puberty.

Another study to be published soon also indicates a problem with ICSI and the sex chromosomes. Andre Van Steirteghem of the Free University in Brussels (VUB), who originally developed ICSI, found through tests on amniotic cells that in ICSI pregnancies there are three times as many sex chromosome abnormalities, including loss of the Y chromosome. But the risk was still very low-only 10 out of almost 1600 fetuses created by ICSI had the defects.

That doesn't mean there isn't a problem, says McElreavey. Men with Y chromosome microdeletions make up just a small fraction of those using ICSI, but they might be largely responsible for offspring with Y chromosome losses. If so, then the technique may be too risky to use on them. Every fertility clinic should be checking for these microdeletions, McElreavey says. 'We need much greater follow-up of these men.' ICSI has been under fire ever since it was introduced. While most studies suggest the rate of abnormal births is no higher than usual, some indicate that it's twice as high (New Scientist, 22 November 1997, p 5). Worldwide, 35,000 ICSI babies were born in 1998. Rachet Nowak, Melbourne

Good for parents, bad for baby

SINCE its introduction in the early 1.990s, controversy has dogged the IVF technique called intracytoplasmic sperm injection. ICSI involves injecting a single sperm into an egg and is used mainly when men cannot fertilise an egg because their sperm count is too low or their sperm abnormal. A series of recent studies has associated ICSI with infertility in children, chromosomal abnormalities, birth defects and delays in mental development. The latest research suggests that children created by ICSI have a raised risk of being born with Turner's syndrome or ambiguous genitalia (see p 11). So just how safe is ICSI? The truth is we don't know. It's a sad fact that we know very little about the long-term side effects of any IVF technique. Most follow-up studies have been short-term and focused on only small numbers of children.

To understand the impact of ICSI and other IVF methods, we need long-term, large-scale research. For couples undergoing IVF, this would mean consenting to long-term follow-up of their children. Governments will not only have to flnd the money for research but take another look at privacy laws surrounding IVF. Many countries introduced these laws to prevent discrimination against testtube babies, but they have seriously hampered epidemiological studies. It's time to strike a better balance between protecting the privacy of this generation of IVF children and the health of the next.

Can't Ape Cloning

A HIGH percentage of cloned monkey embryos that look healthy are really a "gallery of horrors" deep within, says a researcher at Advanced Cell Technology, the company that last month published the first paper on cloned human embryos.

This could mean that there is something unique about primate eggs that will make cloning monkeys or people far more difficult than cloning other animals. At the very least, the experiments show that there's a lot to learn before primates can be cloned.

Tanja Dominko, who presented the results last week at a conference in Washington DC, did the work before joining ACT, while she was working for the reproductive biologist Gerald Schatten at the Oregon Regional Primate Research Center in Beaverton. Several groups have been trying for years to clone monkeys, but while the embryos look normal, no one has ever got them to develop further.

To try and figure out what was going wrong, Dominko looked at 265 cloned rhesus macaque embryos created by nuclear transfer-plucking out an egg's nucleus and then adding a nucleus ftom a donor cell. She followed development of the embryos through several divisions, ftom the two-cell stage until the 32-cell stage.

Though they appeared superficially healthy, the cells in the vast majority of Dominko's embryos did not form distinct nuclei containing all the chromosomes.

Instead, the chromosomes were scattered i unevenly throughout the cells. "The surprising thing is that these cells keep dividing," says Dominko. Some embryos developed to the stage known as a blastocyst, but by day six or seven they had started to look abnormal.

The cloned human embryos created by ACT didn't even get this far. Only one reached the six-cell stage (New Scientist, I December, p 4).

Dominko says that the trauma of removing the nucleus from the egg might be what triggers the defects. Eggs whose nuclei are removed and then put back inside show the same abnormalities, as well as evidence of programmed cell suicide. "This is not to say that normal embryos can't be made, but not on a regular basis,' says Dominko.

Ian Wilmut, who cloned Dolly the sheep, told the conference that Dominko's results were not surprising in the light of experience of nuclear transfer in mice and cows. Even in these animals the success rates are not high, so the phenomena observed by Dominko probably occur in them as well-it's just that everyone focuses on the few successes, he says.

Even so, researchers hoping to publish work on nuclear transfer in humans may now have to come up with better evidence that embryos are healthy. William Haseltine, editor of the journal in which ACT published details of its cloned human embryos, now agrees that pictures alone aren't enough. Sylvia Pagin Westphat, Boston

Melting away The "Snowball Earth" idea is starling to feel the heat

DID the oceans freeze 700 million years ago, turning the Earth into a huge ball of ice? Controversy over the "Snowball Earth" theory is being stirred up by new findings that suggest life went on as normal when the oceans were supposedly covered with ice and almost lifeless. Geochemist Martin Kennedy and sedimentologist Nicholas Christie-Blick studied rocks from three continents and found no sign that life was affected at this time. According to Christie-Blick, of the LamontDoherty Earth Observatory in New York, their results prove that the oceans did not freeze over. "There was a lot of sea ice," he says, "but life went on [as normal]."

Harvard University's Paul Hoffman and Daniel Schrag proposed their Snowball Earth hypothesis in 1998. They suggested a runaway cooling mechanism that covered the oceans with ice sheets and brought biological activity to a near stop for millions of years during the Neoproterozoic period (New Scientist, 6 November 1999, p 28).

This striking idea appeared to solve several geological puzzles, including signs that glaciers had existed in the tropics. There's also a unique sedimentary layer covering the debris from Neoproterozoic glaciation. It's called the "cap carbonate" layer, and it has a strange carbon signature. When marine plants photosynthesise, they slightly prefer carbon-12 to carbon-13, leaving a small excess of carbon1 3 behind in seawater and the rocks that precipitate from it. The more

life there is, the more carbon-13. But cap carbonates have a strikingly low ratio of carbon-13 to carbon-12, indicating minimal biological activity. Hoffman and Schrag had only studied rocks from before and after the glacial period, however, so Kennedy and ChristieBlick set out to find rocks that formed during the big freeze. If ice sheets sealed the oceans and brought life almost to a standstill, sediments from that period should contain less carbon-13. But Kennedy and Christie-Blick found the opposite. Samples from Africa, Australia and North America had plenty of carbon-13, as did the oldest cap carbonates. "The ecosystem was happy," says Kennedy. 'So was there really an ice sheet?' Christie-Blick is even more pointed. "If the geochemical part doesn't work, all the rest of it doesn't work either. The data makes the snowball hypothesis incorrect, at least as initially published." Their findings match the latest results from computerised climate models, in which equatorial oceans stubbornly resist freezing over (New Scientist, 9 June, p 12). Schrag doesn't necessarily reject Kennedy and Christie-Blick's new data, but his interpretation is different. He now thinks that patches of open water persisted even during the global deep-freeze. That would have radically changed the ocean's carbon chemistry as it absorbed large amounts of carbon dioxide from the atmosphere-a factor he says Kennedy and Christie-Blick ignored. "They're making simplistic predictions," says Schrag, "so their analysis is just plain wrong." Robert Adier

More at: Geology (vot 29, p 1135)

Go-faster Universe may just be a trick of the light

SIGNS that the expansion of the Universe is accelerating may be an illusion. Scientists think particles called axions might create the mirage by hijacking light as it travels the cosmos. Three years ago, cosmologists found that very distant supernova explosions are fainter than they should be. This suggested that space had stretched more than expected as the light sped towards Earth, so it had to travel farther. The Universe appeared to be expanding faster and faster (New Scientist, 11 April 1998, p 26).

With scientists struggling to explain what force could drive this acceleration, a team in the US has now come up with an alternative explanation. They say the light from distant supernovae is dim because some photons tum into axions on their way to Earth. Axions are hypothetical particles predicted by several leading theories of particle physics. Even if they exist they'd be very difficult to detect because they rarely interact with other matter. But Csaba Cs6ki of Los Alamos National Laboratory in New Mexico says that if axions had a tiny mass-10-21 times that of the electronthey would interact with light in the tangled magnetic fields of intergalactic space. As photons travelled to Earth, this interaction would persuade a fraction of them to flip into axions themselves, making them undetectable.

With his Los Alamos colleague John Terning and Nemanja Kaloper of Stanford University in California, CsSki has calculated that about a third of the visible photons from the most distant supernovas would effectively vanish.

"We shouldn't just accept on face value that the Universe Is accelerating," Cs6ki concludes. 'There are alternative and viable explanations to the supernova observations based on particle physics." Hazel Muir More at: wwwarxivorg/abs/hep-ph/0111311

Glacier meltdown a shock for scientists NZ Herald Dec 2001

Confirmation that three of Antarctica's biggest glaciers are rapidly thinning has come just a month after a large iceberg broke away from one of the glaciers in the Amundsen Sea. The Pine Island, Thwaites and Smith glaciers, which account for about one-third by volume of the West Antarctica Ice Sheet, have lost as much as 45m of thickness over the past 10 years. Collectively they have lost nearly 157 cu km of ice to the ocean, enough to raise global sea levels by 0.04cm. Scientists used data collected by the European Remote Sensing satellites between 1991 and this year to measure the glaciers. The results, presented this week to the American Geophysical Union, contradict previous studies that suggested the volume of ice was accumulatmg in that part of Antarctica. "What is really important is we see these glaciers changing with tiine in a surprising manner," said Eric Rignot, a research scientist with the National Aeronautics and Space Administration's Jet Propulsion Laboratory. In places near the Amundsen Sea, the glaciers thinned by as much as 45m. The three glaciers sit on bedrock, located below sea level, and act as drainage channels frozen rivers of ice for a portion of the sheet. At their present shrinkage rate, they could begin to float within 150 years. A month ago, the US National Ice Centre had reported that an iceberg 233 square miles (603 sq km) in area had splintered away from the Pine Island Glacier. Icebergs B-21 was detected by US Defence Department satellites. If the glaciers were to melt completely, they could have dramatic effects on a global scale. "If it were to collapse, it would raise global sea levels by over one metre," said Andrew Shepherd, a research fellow At the Centre for Polar Observation and Modelling at University College, London. Mr Shepherd cautioned that it would take as long as 1500 years for the three glaciers to completely vanish. While a long time for a human, it is a blink of the eye in the world of glaciation, where time periods are measured in the tens of thousands of years, he warned. "These are very rapid events," Mr Shepherd said of the melting icebergs. The glaciers are shrinking because they are losing more ice to the ocean Urn can be replenished by snowfall. VVhy that occurs is not certain, although scientists suspect global warming is the culprit. A 1991 study indicated ice was pilnig up in Antarctica, even as global mean temperatures rise. AP

Cloning battle may be history NZ Herald 26 Jan 2002 New Sci.

American scientists have made a discovery that could make cloning for scientific purposes unnecessary.

It miGHT turn out to be the most important cell ever discovered. It's a stem cell found in adults that can turn into every single tissue in the body. Until now, only stem cells from early embryos were thought to be able to do this. If the finding were confirmed, it would mean cells from your own body could one day be tamed into all sorts of perfectly matched replacement tissues and even organs. If so, there would be no need to resort to therapeutic cloning cloning people to get matching stem cells from the resulting embryos. Nor would you have to genetically engineer embryonic stem cells (ESCS) to create a "one cell fits all" line that does not trigger immune rejection. The discovery of such versatile adult stem cells would fan the debate about whether embryonic stem cell research wasjusttled. "The work is very exciting," says Ihor Lemischka of Princeton University. "They can differentiate into pretty much everything that an embryonic stem cell can differentiate into." The cells were found in the bone marrow of adults by Catherine Verfaillie at the University of Minnesota. Extraordinary claims require extraordinary proof, and though the teain has so far published little, a patent application seen by New Scientist shows the team has carried out extensive experiments. These confirm that the cells dubbed multipotent adult progenitor cells, or MAPCs have the same potential as ESCs. "It's very dramatic, the kinds of observations [Verfaillie] is reporting," says Irving Weissman of Stanford University. "The findings, if reproducible, are remarkable." At least two other labs claim to have found similar cells in mice, and one biotech company, MorphoGen Pharmaceuticals of San Diego, says it has found them in skin and muscle as well as human bone marrow. But Verfaillie's team appears to be the first to carry out the key experiments needed to back up the claim that these adult stem cells are as versatile as ESCS. Verfaillie extracted the MAPCs from the bone mar-row of mice, rats and hwnans in a series of stages. Cells that don't carry certain surface markers, or do not grow under certain conditions, are gradually eliminated, leaving a population rich in MAPCs. Verfaillie says her lab has reliably isolated the cells from about 70 per cent of the loo or so human volunteers who donated marrow samples. The cells seem to grow indefinitely in culture, like ESCS. Some cell lines have been grokving for almost two years and have kept their characteristics, with no signs of ageing, she says. Given the right conditions, MAPCs c, an turn into a myriad of tissue types: muscle, cartilage, bone, liver and different types of neurons and brain cells. Crucially, using a technique called reb7oviral marking, VerfaiUie has shown that the descendants of a single cell can turn into all these different cell types a key experiment in proving that MAPCs are truly versatile. Also, Verfafflie's group has done the tests that are perhaps the gold standard in assessing a cell's plasticity. She placed single MAPCs from humans and mice into early mouse embryos, when they are just a ball of cells Analyses of mice born after the experiment reveal that a single MAPC can contribute to all the body's tissues. MAPCs have many of the properties of ESCs, but they are not identical. Unlike ESCs, for example, they do not seem to form cancerous masses if you inject them into adults. This would obviously be highly desirable if confirmed.

"The data looks very good, it's very hard to fmd any tlaws," says Lemischka. But it still has to be independently confirmed by other groups, he adds. Meanwhile, there are some fundamental questions that must be answered, experts say. One is whether MAPCs really form functioning cells. Stem cells that differentiate may express markers characteristic ofmany different cell types, says Freda Miller, of McGill University. But simply detecting markers for, say, neural tissue doesn't prove that a stem cell really has become a working neuron. VerfaMie's findings also raise questions about the nature ofstem cells. Her team thinks that MAPCs are rare cells present in the bone marrow that can be fished out through a series ofenriching steps. But others think the selection process actually creates the MAPCs. "I don't think there is 'a cell' that is lurking there that can do this. I think that Catherine has found a way to produce a cell that can behave this way," says Neil Meise of new York University Medical School.

HAVE we found the ultimate stem cell? One that can deliver all the benefits of embryonic stem cells without having to destroy a potential human life to save an existing one? It's too early to tell, say stem cell researchers. While they are excited about the potential of an adult stem cell such as Verfaillie's, most insist that research with embryonic stem cells must continue, because nobody can possibly know right now which option is better. And it might be worth it for more than one reason, says Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. Many scientists Ver-faMie included are patenting their discoveries, which could hinder their widespread use. We need to keep all options open, he says. But in the United States, federally funded researchers have only just been allowed to work with a limited number of ESC lines. Opponents ofsuch research, who have long touted adult stem cells as an alternative, are likely to seize upon Verfaillie's results. As Richard Doerflinger ofthe US Conference ofcatholic Bishops puts it, the only reason many lawmakers have felt compelled to "cross the moral line" in backing ESC research is because they believe it is the only way to get the full benefits. Indeed, Erik Parens, ofbioethics thinktank The Hastings Centre, believes the discovery could have a negative impact, letting the US dodge the debate over embryonic research. The discovery could affect the cloning laws being drawn up around the world. While banning reproductive cloning, countries such as Britain have permitted therapeutic cloning because doctors could use it to obtain ESCS. But if every human being already has a reservoir of stem cells with similar potential, should research continue into a technique that could easily be abused by those eager to create the first cloned babies? NEWSCIENTIST

Mexican standoff over GM NZ Herald 26 Jan 2002
A chance discovery in Mexico has re-ignited the genetic foods debate, as Zarembo reports.

OLGA Toro Maldonado was short on corn seed and slightly curious. In the spring of 1998, alongside the corn she raised on her hillside plot, she planted 60 kernels she purchased from the government store. "The corn looked good," she recalls, so the next year she planted a cross between the two species. The harvest was smaller than the year before one ear per stalk rather than the usual two but the corn was tasty enough. She ground it into flour for tortillas and fed the kernels to her chickens. A few scientists stopped by in autumn 2000 and took away samples from her most recent harvest. They returned a week later with some disturbing news. Maldonado's corn contained transgenes genes from bacteria and other organisms, artiflcially introduced to make the corn resistant to herbicides or insects. Maldonado, aged 40, heard the word "contamination" and began worrying about her six children, her chickens and whether the pollen from her corn had spread. "I feel guilty," she says. "But another woman told me she planted it, too. I'm not the only ignorant one. We don't know the damage we can do." The head scientist was Ignacio Chapela, a 42-year-old Mexican microbial ecologist at the University of California Berkeley. His team collected corn from the mountains of Oaxaca, in southern Mexico, and found several samples contained transgenes. The finding was startling because the Mexican Government bans the planting of' genetically modified com. And the agriculture industry has long contended that contamination from GM crops was unlikely. "I was dumbfounded," Chapels says. "I knew it was a difficult political fray we were getting ourselves into." There is no evidence that GM corn is dangerous for human consumption. Chapels and his allies are concerned instead that GM corn might pose a threat to the crop's biodiversity. Mexico, where corn was domesticated 10,000 years ago, is what scientists call the crop's "centre of genetic diversity" a repository of traditional varieties.

GM corn, with its engineered advantages, could theoretically overwhelm indigenous types. That would leave breeders without a source of pristine seed if a plague struck corn crops elsewhere. "World food security depends on the availability of this diversity. Having it contammated is something humanity should worry about" says Chapels. Mexico, the corn-consuming capital of the world, has been cautious about corn. Congress banned GM com crops in 1998, even while allowing GM cotton and tomatoes. The present administration has been reconsidering the ban in an effort to improve agriculture and attract investment. A combination of decades of bad agricultural policy and falling trade barriers with the United States has turned Mexico into an importer of its staple food: six million tonnes of com a year come from the United States. A panel of scientific advisers recently recommended opening northwest Mexico, which has none of the traditional strains of com, to transgenic corn crops. "Mexico as a country cannot exclude itself from biotechnology," says Victor Manuel Vilalobos, the Under-Secretary of Agriculture. "It is not an intelligent position to say that because there are risks *e won't

Chapela's revelation that GM com is growing in the hills of Oaxaca is an embarrassment to the Mexican Government to say the least. After Chapela's paper appeared in the scientific journal Nature in November, a Greenpeace activist declared the contamination "a worse attack on our culture than if they had torn down the cathedral of Oaxaca and built a McDonald's over it".

Greenpeace began urging indigenous groups in Oaxaca to sue the Federal Government. Eighty scientists from 12 countries demanded the Goveniment take steps to contain the damage. The Government's own tests found transgenes in Oaxaca and neighbouring Puebla, as had Chapela, but Villalobos maintains that more detailed studies may refute Chapela's findings. Meanwhile, he warned Chapela, in a letter dated November 28, that the Federal Government "will take measures ... to redress the great damages, as much to agriculture as to the economy in general, that ... your publication might have caused". The economic damage stems from a bizarre irony: even though Mexico bans GM corn crops on its soil, a third of its imported US corn is transgenic. If public sentiment turns against GM corn, officials argue that having to import only non-GM corn would raise prices for consumers. Such corn is the most likely source of the genetic contamination. It arrives in sacks mixed with umnodified varieties and often ends up at Govenunent stores, where it is sold as food for the poor and their animals. US biotech firms instruct farmers to keep buffer zones around GM corn to prevent foreign genes spreading, but the stores of Oaxaca, where peasant farmers shop, have no warnings at all. Maldonado's corn grows near a hilltop, with pine-green mountains in the distance. As she points out which corn stalks are crosses and whirh are pure, a strong wind sweeps by strong enough, perhaps, to spread pollen to nearby plots. Indeed, Chapela found transgenes on farms where store-bought corn was never planted. As word of his discovery trickled through Oaxaca, villagers feared the Goveniment was going to burn their fields or prosecute farmers.

At the Government store in Calpulapan, the 59-year-old clerk Elfego Martinez Perez, claims the corn "can cause a disease called cancer". That hasn't kept him from selling it or eating it himself Chapela's detractors, including many scientists, accuse him of exaggerating the dangers. The term "native corn" is a misriomer; they say, because farmers have been modifying the genetic makeup of corn through selective breeding for thousands of years. 'We've got a lot of utopian idealists worried about contamination of the old corn varieties with the new. This is corn pletely idiotic, the way it has been presented," says Norman Bourlag, a Nobel laureate and founder of the International Wheat and Maize Improvement Centre near Mexico City. Since none of the genes found in the GM com was active, the corn didn't exhibit the traits engineered into it. Even if it did, some critics argue, the GM corn wouldn't necessarily have an advantage because it was engineered to grow well in the United States, not Mexico. "Just the presence of one new gene is not going to destroy maize in Mexico," says David Hoisington, head of the Applied Biotechnology Centre at the wheat and maize centre. "It's not a threat to biodiversity. It's just one gene among 50,000 to 60,000 genes." Officials at Monsanto, which holds a patent on at least one of the genes Chapela found, make the same argument. Regardless of which side in the gene wars is correct, one thing is clear: now that transgenic corn has been let loose in Mexico, stopping its spread is next to impossible. Bans on the imports of GM com, as Greenpeace has called for, would accomplish nothing. And what if all the GM corn in Oaxaca magically disappeared. Some of the thousands of Mexican migrant workers who return each year from the United States no doubt carry kernels they reckon might grow well on the hillside back home.

World food security depends on the availability of this divers4. Having it contaminated is something humanity should worry about. lgnacio Chapela microbial ecologist

Will GM vaccine foods prove viable? NZ Herald 26 Jan 2002
Genetic scientists are engineering plants to produce human vaccines. But will consumers take the medicine? Fred Guterl reports.

Watching plants grow was Hugh Mason's idea of a good time. He was always re interested in organic molecules DNA, proteins, in the organisms themselves. But these days he's spending a lot of time fretting over his tomatoes. They grow in pots in a greenhouse at Cornell Universlty's Boyce Thompson Institutte in upstate New York.

At first sight they seem normal but there's something odd about them. What is it, his visitor a few moments of puzzlement. His boyish face and calm demeanour are reassuring in a molecular biologist whose speciality is tarnpering with food. A few years ago he was insertming foreign genes into plants to make them better able to resist drought when a colleague suggested a more exciting possibility: why not find genes that would make common, edible plants produce vaccines against a human disease? That is precisely what Mason is trying to do. The tomatoes he nurtures bear a synthetic gene that causes them to produce a protein identical to the one that serves as a protective shield for the Norwalk virus, which causes stomach ache and diarrhoea. Mice that eat the tomatoes (freeze-dried and powdered) develop irmnune responses to the virus. Later this year Mason hopes to serve his fruit to people, and then test its efficacy by exposing them to the live virus. This research, he hopes, will lead to radically cheaper ways of making and delivering vaccines. If this technology is ever going to see the light of day, Mason and his colleagues will have to perform a similarly radical altering of public attitudes towards genetically modified foods.

When the first GM food products were introduced a few years ago, they were targeted narrowly at farmers (and American farmers at that), to protect crops from insects and herbicides. The next generation, by contrast, is aimed sqarely at consumers. Products being developed in laboratories throughout the world include not only vaccine-bearing plants such as Mason's tomatoes, but also food staples such as rice, corn, soy and other vegetables and vegetable by-products with enhanced nutritional value.

To get there scientists will have to surmount a lot of public disdistrust. In the past few years agro-biotechnology has joined nuclear physics as one of the world's most reviled scientific endeavours. 'The food industry and its regulators are partly to blame: they are guilty of serious bungling, including grossly underestimating the degree to which people and, in particular, Europeans are sensitive to any tampering with what they eat. Dark, unconscious fears about what scientists do is one thing, but who wants to confront them every time you raise a fork? Despite Mason's benevolent neediness, there is definitely somewhat odd sinister, perhaps'. about those bright little tomatoes. "have you figured out what it is?" he asks. "It's the leaves. They're crinkly." Sure enough. unlike the smooth leaves of a normal tomato plant, Mason's are wrinkled, as though they had been dried on the stem. It doesn't affect the taste of the tomatoes or their safety, he explains. "It's just an undesirable result of them becoming transgenic. I'm not entirely sure why it happens. Maybe because they have an excess number of chromosomes. It doesn't happen in all of the plants. Most of them look pretty normal." What are crinkly leaves compared with the potential of tomato vaccines to prevent illness in thousands of children who die each year because they haven't been vaccinated against such commonplace illnesses as diphtheria, diarrhoea, whooping cough, polio and measles? Unlike many conventional vaccines, food-borne ones wouldn't need refrigeration They could be distributed as seeds and grown locally, making them cheaper to deliver to remote Third World vUWes. It's not hard to imagine how much easier and safer it would be to delixfer, say, a tuberculosis vaccine, contained in the genome of a tomato or banana than in a perishable serum that must be injected with a syringe. When, more than 10 years ago, Mason's mentor, biologist Charles Arntzen, first proposed engineering plants to make vaccines, Mason recalls being stunned.

"The plan sounded a bit crazy, but I couldn't think of a reason why it wouldn't work," he says. They chose to start with a vaccine for hepatitis B, which was derived from a gene found in yeast. They spliced the yeast gene on to some plant DNA and used an "agrobacterium" to deliver the genetic material to cells of a tobacco plant. From each cell they cultivated complete plants, extracted leaf cells and examined them with an electron microscope. At last they found what they were looking for: the hepatitis B antigen a harmless protein that, once in a person's bloodstream, would trigger an immune response to thL, disease.

They knew they had engineered a plant that contained the desired yeast gene and that would manufacture the hepatitis B vaccine. The experiment was encouraging, but when the two scientists began talking about their work at conferences, they realised how

naive their original idea of plant-borne vaccines hood been. "'Me idek was, maybe we can produce the vaccine in plants, and then with common agricultural methods you could scale up. If you need a minion more doses, you just plant a few more rows. But it turns out you have to worry about correct dosages and all sort of things like that. You have to treat these plants as pharmaceuticals, not food." Mason and Arntzen have since grown potatoes that express Norwalk v@ and E. col! antigens. They've served the potatoes raw, because cooking might @e the antigens to human test subjects and succeeded in stimulating @une responses. The tests established not only that vaccines can be grown m plants but that they can survive the trip through the stomach to the bloodstream. But much remains to be done before the technology is ready for general use. Scientists don't know how much vaccine a person would need to eat to ensure protection and how often, and how to avoid overdosing. Dosage levels of plant-home vaccines are low, so researchers need to fmd a way to boost them. Eating vaccines might also lead to "oral tolerance", suppressing the immune response and rendering the vaccine impotent. "There's been some really excellent work," says Roger Beachy, president of the Danforth Plant Science Centre in St Louis, Missouri. "But can we really protect people or an@ with these vaccines? It's an open question." Academic research alone isn't enough to answer this question. These research curiosities will fimt have to be developed into potential products, which wfll have to run the gauntlet of approvals and trials for new medicines. The problem is that the public distaste for GM foods has made it difficult to. find the investinent needed to develop these products in the first place. Europe is the centre of opposition. Europe's antipathy over GM foods dates back to the late 1980s, when the German chemical giant Hoechst collided with environmentalists over its plans to use then leading-edge GM techniques to manufacture insulin at a plant in Frankftwt. Even though similar methods were already used in the United States, Germany's influential Greens could not be convinced that the plant was safe. It was 10 years before it was finally allowed to open. 'The insulin affair paled, however, next to the fiasco of St Louis-based Monsanto Corp. It blundered into the European market with GM soy varieties tailored to benefit American farmers. French activist Jos Bov led a group that stormed a Monsanto plant in the Brazilian town of Nao Me Toque, trashing several hectares of transgenic soybeans. The police simply looked on as the experimental plots were turned into genetically modified mulch. The firm eventually launched a publicrelations campaign explaining the merits of GM foods, but it was too late. "The message was never fuly explained," says David Hughes, professor of food marketing at Imperial College, London. "People just thought that the company was trying to pull the wool over their eyes." Monsanto's perceived arrogance was aR the mor-e because the mad-cow scandal had made Europeans leery of the food industry in general. The Monsanto case was only one of the food industry's screw-ups. The US Environmental Protection Agency made the dubious decision to approve the Starlink variety of GM com, made by agrosciences firm Aventis, for animals but not people. In 2000 the corn was found in the products of fast-food restaur-ant Taco Bell. The incident made regulators wary, slowing approvals for research trials. ProdiGene, a Texas-based biotech firm formed in 1996 to develop foodhome vaccines for livestock, saw its funding from venture capitalists virtually dry up overnight.

"Venture capitalists got cold feet," says chief scientist john Howard. "They started asking, 'Are you ever going to be able to market this stuff? "'

ProdiGene fared better than the Cambridge, England-based Axis Genetics, which developed edible vaccine" for hepatitis B. Two years ago the firm failed to secure financing for clinical trials and went belly up. "Public anxiety was reflected in investors refusing to have anything to do with GM plants," says former CEO Cubit. Axis' assets and intellectual property were sold to Dow, the IOS chemical and agriculturesciences company. Dow, as well as several other large agrosciences firms, refused to discuss its activity in GM foods for this article. its shyness about publicity can be explained in part by the need to keep trade secrets, but the negative example of Monsanto in the 19gos has clearly put these firms on the defensive. European politicians have also proceeded cautiously. Even though many ministers take a favourable view of GM foods, the EU has had a virtual moratorium on new GM food products for the past three years. In an effort to reassure consumers, EU ministers are instituting rules requimg all GM products to be labelled as froni next year. "Unless we restore consumer confidence in this new technology, genetic modification of food is dead in Europe," EU Agriculture Minister Tony Van der Haegen bas said. But the issue is unlikely to rest there: the United States opposes labelling as unworkable, and the French Govenunedt is talking about new laws that deal with issues of liability. "This isn't just French recalcitrance it's a big political problem for people in France," says Julia Moore, a scholar at the Wilson Centre in Washington, DC. "In Europe, there is no public trust in govermnent ability to keep food safe." To re-establish that, the food industry will have to risk confronting the public's fears. Niall FltzGerald, chairman of European rood company Unilever, which yanked its GM food products when the crisis broke a few years ago, has shown some willingness to reconsider.

'The mistake that has been made with GM crops and food is the failure to reach the consumer " he said in a speech this month. "We need to begin afresh. That doesn't mean opinion. It means setting a lead communicating directly and honestly with the consumers and answering all the questions that people have." A cynic might say that Fitzgerald is merely an opportimist because the price of non-GM cooking oils has risen recently, Unilever would save money switching now to GM brands. Another kind of cynic might point out the children dying from lack of vaccines who might be saved if investment in foodhome vaccines were more forthcoming. That's about how polarised the issue of GM foods has become. NEWSWEEK