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NS 16 mar 02

Hidden dragon American biotech has nothing to fear from China's clones

DESPITE the years of hype about cloning changing the face of medicine, no scientist in the West that we know of has yet grown a cloned human embryo to the stage where it could yield any potentially useful stem cells. Has an unknown fertility expert in China really cracked the problem (see p 6)? Until Lu Guangxiu's research is published and scrutinised by other experts, it's impossible to be certain. What's clear is that in the West, especially the US, Lu's claims make perfect ammunition for snipers on both sides of the moral divide over embryo research. Opponents of the research can now brand embryo cloning as the kind of repugnant activity that non-democratic nations dabble in. American biotech lobbyists campaigning for unfettered human embryo research can spread alarm about a communist nation surging ahead to commercialise a key medical technology. Both views are absurdly simplistic. The reason Chinese scientists are busy planting genetically modified crops and forging ahead in stem cell research is the reason both these activities flourish in the American private sector: there are few regulations holding them back. In this sense, China's freewheeling approach to "progress" shares more with laissez faire capitalism than Mao's Little Red Book. And the fact that Britain has also said yes to limited human embryo cloning suggests it can hardly be a communist plot.

Which is not to say there aren't valid concerns about the way China is embracing other aspects of biotechnology. One is eugenics. In 1995, China passed a law forbidding couples with genetic diseases from marrying unless they agree to be sterilised or take long-term contraceptive measures. Geneticists in China are also more receptive to the idea of using genetic screening to prevent children with disorders being born.

There is no suggestion that the Chinese scientists involved in the cloning research share this attitude or are guilty of any wrongdoing. But, as reported, their claims do raise ethical questions. The team says that only 5 per cent of its cloned human embryos grow to the crucial blastocyst stage, where stem cells can be isolated. And the team appears to be claiming that it has cloned dozens of these human embryos. Taken together, this suggests the researchers have used up hundreds, perhaps thousands, of human eggs in their research to date. In the West, such numbers are unthinkable because donors are scarce. But even if China has found a way to persuade large numbers of women to donate eggs for cloning research, this is not the space race. There is no imminent prospect of the US sliding into the biomedical dark ages if it fails to counter China's clones with ones of its own. Partly this is because the future value of clones to medicine remains unclear. Neither the Chinese team nor any other researchers have so far discovered how to turn ordinary embryonic stem cells, let alone ones from cloned embryos, into safe and effective treatments for human patients. Indeed, judging from American scientists' early attempts to use embryonic stem cells to treat mice, it could be years before we see even the credible beginnings of such treatments. Few of the stem cells injected into the sick animals turned into the immune cells the animals lacked.

And stem-cell therapy will never be a practical proposition if it requires embryos to be cloned every time a patient needs treating. In the short term, scientists may need to carry out limited human embryo cloning, but only so they can discover how to clone tissues without creating embryos.

Where does this leave stem cells taken from adult tissues? As pro-life campaigners constantly remind us, they get round the key moral concerns. Unfortunately, this science too is at a raw and early stage. A team in Minnesota claims to have used bone marrow stem cells to repair brain damage in rats (see p 12). If replicated, that is promising. But long-term success with these cells is no foregone conclusion. Confusion rages over just how versatile and safe they are.

Last summer George W. Bush limited American government funding of embryonic stem cell research to studies using existing cell cultures. Later this year the US Senate is likely to vote to ban American scientists from creating any cloned human embryos and perhaps even from importing cells from such embryos. But even if this becomes law, all will not be lost for American biotech industry. American scientists will still be able to study adult stem cells and stem cells from non-cloned embryos. And there will be nothing in US law to stop American companies funding human cloning work in labs overseas and reaping the financial rewards of any patent@ble technologies that emerge. Americans went to Scotland to buy up the Dolly technology. In today's globalised marketplace China is not so very far away.

The race for a cure Who will benefit from the rapid advances in therapeutic cloning?

GET ready for a new wave of medical tourism-desperately ill people heading to countries where cloning and embryonic stem cell technologies offer them treatments that are forbidden at home.

That could be the consequence of the growing division between countries that have given these technologies the green light and others that are trying to prohibit them. Therapeutic cloning, for instance, promises to yield new-if expensive-treatments for everything from Alzheimer's and Parkinson's to diabetes and autoimmune disorders.

Last week news leaked out that Chinese scientists had made a big advance, harvesting embryonic stem cells (ESCS) from dozens of cloned human embryos. Yet while Britain is granting the first licences to carry out similar research, the US is pushing the UN to ban therapeutic cloning and Australia might block the creation of new ESC lines. If the trend continues, people who live in anti-ESC countries will have no option but to go abroad if they needed treatments that involve therapeutic cloning, says Robin Alta Charo, a legal expert at the University of Wisconsin-Madison. "If you want it, you better have the air fare," she says.

While a UN ban is unlikely, the US government is not only discouraging research on its own soil, but is also considering laws that prohibit the import of cells derived from cloning. This would stop American doctors from offering any new treatments developed elsewhere.

The controversy centres on whether it's justified to destroy five-day-old human embryos to obtain ESCS. And there's an additional worry surrounding therapeutic cloning, in which the ESCs would be derived from a cloned embryo of a patient to yield immune-compatible tissues: the technology could be hijacked by rogue scientists wanting to create cloned babies.

As long as the benefits remained largely theoretical, the debate had seemed deadlocked. The few cloned human embryos that had been created hadn't grown past a few cells, far too early to harvest ESCS. Then The Wall Street journal reported that Lu Guangxiu of the Xiangya Medical College has derived dozens of ESC lines from cloned human embryos at the 200-cell stage. At least three other Chinese groups are rumoured to have made similar or greater advances.

The Chinese team appears to have benefited from looser regulation, which allowed Lu to collect many human eggs for her research. The difficulty of obtaining eggs has held up research in the West. Although none of the results has appeared in a peerreviewed publication, scientists familiar with the Chinese work told New Scientist the claims are very credible.

Experts believe major papers have been, submitted to Western journals. "I hope they,, are published soon," says Xiangzhong Uerry) Yang, a Chinese-born cloning scientist now, at the University of Connecticut in Storrs. 'Their work is the most adv@nced out there and they should let the world know about it."

Meanwhile, researchers at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, have just shown for the first time that therapeutic cloning and genetic therapy can be used together to partially correct a serious immune defect in mice. The team obtained ESCs from cloned embryos created from the mice's tail cells, corrected the genetic defect in the cells and injected the new cell line back into the mice.

The study is an important proof of principle. Team member William Rideout thinks that if the science continues to advance at such a blistering pace, critics and lawmakers are bound to change tack. "If we get good and effective treatments in animals, it will overwhelm the opposition,' he says. "How could you remain against it?"

But it might be too late by the time that happens, warns Robert Lanza of Advanced Cell Technology based in Massachusetts. "China or another country may lock up all the key intellectual property in the field." Philip Cohen, San Francisco

Think twice Banning embryonic stem cells might be a bad idea

WHILE therapeutic cloning is storming ahead, hopes that adult stem cells could be as fertile a source of replacement tissue as embryonic stem cells have taken a blow. Studies apparently showing that stem cells taken from adults can develop into a variety of tissues may have been flawed.

This warning comes from two groups, one led by Austin Smith of the University of Edinburgh and the other by Edward Scott of the University of Florida in Gainesville. They found that rather than forming a range of tissue types by themselves, adult stem cells may be forming abnormal hybrids with embryonic stem cells that could be mistaken for pristine new tissues.

"We are not saying that those findings are wrong," says Naohiro Terada of the Florida team. But researchers shouldn't conclude that their stem cells can form different tissue types without checking whether fusion is the cause.

This is just the latest of a series of setbacks to adult stem cell research. In February, one group largely retracted a previous claim that muscle stem cells could give rise to blood cells. Another failed to reproduce earlier studies claiming neural cells could turn into blood cells.

These results come at a politically important time, as countries such as the US and Australia are currently drawing up new laws on the use of embryonic stem cells (ESCs). Many people are opposed to ESC research because it involves destroying human embryos, and argue that adult stem cells show so much promise there is no need to mess around with embryos.

Now, however, it will be much harder for critics and scientists to argue that this promise is real. "It's incumbent upon us to prove whether or not fusion is responsible for [what] we have called 'plasticity'," says Diane Krause of Yale University.

The Edinburgh and Florida groups grew neural and blood stem cells together with ESCs, mimicking earlier experiments iri which neural stem cells grown this way were later shown to turn into various tissue types when injected into embryos. Both the neural and blood stem cells did indeed seem to revert to a blank-slate state.

But closer examination revealed that the cells behaved that way because they had fused with the ESCS. And when one of the groups injected these abnormal fused cells into mouse embryos, a few of their descendants were found to have contributed to different tissues throughout the bodies of the adult mice. That's a cause for concern, because this is seen as the ultimate test of a stem cells' plasticity.

Experts disagree on how significant the results are, however. Krause contends that the way both groups did their experiments encouraged the formation of fused cells. And the authors themselves admit that fusion is a very rare event.

Catherine Verfaillie of the University of Minnesota argues that the adult stem cells she's discovered form too high a proportion of tissues when injected into mice for this to be due to rare fusion events. Verfaille's work, revealed by New Scientist (26 January, p 4), is considered some of the most promising to date. And Terada agrees that the way she carried out her experiments suggests fusion wasn't involved. Sylvia Pagin WestphaL Boston More at: Nature (DOI: 101038/nature729 and 10JO38/nature7301

The natural choice Organic food has more of what it takes to keep you healthy

EATING organic food may help reduce your risk of heart attacks, strokes and cancer. The finding will reignite the debate over its health benefits and may force regulatory agencies to reconsider their position.

Until now there has been little scientific evidence to suggest that organic food is any healthier than conventional produce. The head of the British Food Standards Agency, John Krebs, has gone so far as to say it is no better. But John Paterson, a biochemist at Dumfries and Galloway Royal Infirmary, criticises Krebs for making such statements "on the basis of very little information".

Now Paterson and a team from the infirmary and the University of Strathclyde have found that organic vegetable soups contain almost six times as much salicylic acid as non-organic vegetable soups. The acid is responsible for the anti-inflammatory action of aspirin, and helps combat hardening of the arteries and bowel cancer.

"Eating organic may be good for you," says Paterson. "I'm not an evangelist for the organic food movement, but there was a fairly substantial difference."

The average level of salicylic acid in 11 brands of organic vegetable soup on sale in Britain was 177 nanograms per gram, compared with 20 ng/g in 24 types of nonorganic soup. The highest concentration of the acid, 1040 ng/g, was found in carrot and coriander soup made by Simply Organic based in Bilston Glen, Scotland, while it was not detectable in four traditional soups made by Scottish company Baxters.

Salicylic acid is produced naturally in plants as a defence against stress and disease. This could explain why levels are higher in organic vegetables, which are generally grown without protection from pesticides. Earlier research by Paterson's team discovered significantly higher concentrations of the acid in the blood of vegetarian Buddhist monks compared with that of meat-eaters (New Scientist, 7 July 2001, p 27).

The Food Standards Agency now promises to study the new evidence. 'We are aware of the suggested benefits of high levels of salicylic acid and will look at what the report has to say," says a spokeswoman. Rob Edwards More at: European Joumal of Nutrition (vol 40, p 2891

Early Learning
lt took more than a hectic social life to build a bigger brain

WHY did our primate ancestors get so smart so fast? The most popular idea is that social living was the key to shaping our larger brains. Now this is being challenged by a study which suggests that solving the dayto-day problems of finding food had just as big an effect.

"We should perhaps reconsider the view that a single selection pressure favoured enhanced brain size," says evolutionary biologist Simon Reader at Cambridge University. His study, conducted with Kevin Laland, suggests that a range of factors, not just the demands of group living, favoured bigger brains. There are two main theories of what propelled the massive expansion of our ancestors' brains. One blames it all on society. Living in extended family groups makes it easier to defend feeding sites and spot predators. But predicting how others will react to different situations and keeping track of alliances and rivalries requires extra brainpower. The other theory says ecological challenges were more important: using a rock as a tool to crack a nut or remembering which trees are in fruit at a particular time of year is easier if you are smarter, regardless of whether you live in a group.

Reader and Laland pooled data from around 1000 published studies on 116 primate species. By looking at different species' tool use, their innovative behaviours and how individuals learned from others, they set out to discover if any characteristics of social life or the environment were particularly associated with cleverness.

Their analysis confirms that having a bigger brain makes you generally smarter. But no single factor stood out as being more important than the rest. Crucially, primates living in larger groups were no better than others at learning from their peers.

This suggests that group living may not be so special after all. "It is likely that multiple sources of selection favoured the evolution of large brains," says Reader. Not everyone agrees. "Once you've got the machinery in place, it's really a matter of software design to apply it to other things," says evolutionary psychologist Robin Dunbar of Liverpool University. He thinks the results are still consistent with the idea that social intelligence came first, with other skills and abilities following later.

Reader admits that he can't say for certain whether ecological intelligence or social intelligence came first. But he points out that most of the innovative behaviours seen by previous researchers concerned finding food, not dealing with others. "I do not think we can neglect ecological demands."

But Robert Seyfarth of the University of Pennsylvania argues that, unlike other animals, primates' most impressive intellectual talent is their ability to form complex social relationships. He suggests that other abilities,considered by Reader and Laiand could have links to social skills that aren't obvious. "This study will make us think about what exactly we mean by 'social intelligence'," he says. James Randerson More at: Proceedings of the Notional Academy of Sciences (DOI: 101073/pnas.062041299)

Under your skin Is the stem cell everyone's after staring us in the face?

GETTING hold of adult stem cells from patients to treat their diseases might be easier than anyone thought. A team at the University of Iowa claims to have found adult stem cells in the skin that are capable of giving rise to every tissue in the body.

While some scientists are urging caution over the potential of adult stem cells (see p 7), the hope remains that some of them may be as versatile as embryonic stem cells (ESCs) when it comes to making different tissues. Earlier this year, New Scientist revealed that a team at the University of Minnesota had found stem cells in adult

humans that seemed just as plastic as ESCs (26 January, p 4). But obtaining these cells from bone marrow is a painful procedure.

The latest study, in mice, has identified a subset of stem cells in the epidermal layer of the skin that also seem to have broad plasticity. It's a distinct population that can be isolated by sorting cells based on their size and the proteins on their surface.

When researcher Jackie Bickenbach injected these stem cells into early mouse embryos, descendants of the cells could be found in most of their tissues. But mice from embryos injected with a different population of cells from the same skin layer had no descendants of the cells in their bodies.

Bickenbach didn't expect the cells to be so versatile. "I have to tell you, I was pretty surprised," she says. "We now have evidence that they have been living in mice for over a yeal " Her team is trying to find out if there are similar cells in human skin.

Ihor Lemishcka of Princeton University points out that better controls are needed in experiments like this to prove that the apparent plasticity isn't due to abnormal cell fusion (see p 7). But despite these concerns, Neil Theise of New York University says he is confident that good evidence of broad plasticity and therapeutic potential for adult stem cells will continue to emerge. "This is just the beginning," he says.

The University of Minnesota researchers have already gone on to show that their bone marrow stem cells can repair the damage caused by strokes. A team led by Walter Low triggered strokes by tying off a blood vessel in the brains of rats. The resulting brain damage made the animals lose control of their limbs.

A week later, the team injected the bone marrow stem cells near the injury area. Not only did the cells home in on the regions that needed repair, but they also began to express markers typical of functional brain cells. Most strikingly, the rats' ability to move their limbs was largely restored, says Low. He hopes this study will be the first step towards moving the technology into clinical trials. Sylvia Paghn Westphat, Boston

More at: Stem Cells (vol 20, p 21); Experimental Neurology (vol 174, p 11)

Eat what you're given and no arguments

YOU have no right to know where the food you eat ultimately comes from.

That's the ruling of an international body of food experts. lt says governments cannot demand that consumers be told their food's genetic origins-whether a cooking oil comes from beans with a genetically modified ancestor, for instance. The only exception would be when a food turns out to be dangerous-allergenic, for example-and the culprit appears to be a modified gene.

Environmentalists have condemned the decision by a task force of the Codex Alimentarius Commission, a UN panel that rules on issues about international food trade. After a heated debate to agree global rules on "risk analysis of foods derived from biotechnology" at a meeting in Yokohama, Japan, the CAC threw out calls from the European Union to allow governments to demand full genetic "traceability" of GM food. But Bruno Heinzer of Greenpeace says that will "increase the risk of a plant-food equivalent of mad cow disease".

Commission secretary Alan Randell explained the decision, saying that foods increasingly have their origins in GM crops, even though the plants themselves are not directly modified. Traceability would require manufacturers to reveal "the family tree back to the original modified soybean, or whatever", says Randell. "But that is not now foreseen. Instead, some 200 national delegates accepted a much less demanding rule sought by the US, Australia and others.

Disclosure of such genetic ancestors will only be necessary "when a risk to human health has been identified".

"The US will interpret this as meaning you only do the checks after an accident," Heinzer claims. But the same meeting did agree to more stringent tests on food to prevent genes for allergenic proteins from being accidentally transferred during genetic modification of crops. The decision follows two recent scares, one when the gene for a protein that causes Brazil nut allergy got into a GM soya bean under development, the other when a suspected allergen was found in StarLink, a brand of GM corn. Fred Pearce

Test tube trauma A disturbing link between IVF and major birth defects is emerging

WOULD-BE parents might want to persevere with old-fashioned sex for a little longer. before resorting to IVF. One of the 'Most comprehensive studies to dat&suggests that babies conceived by IVF are more than twice as likely to suffer major birth defects as babies conceived naturally.

The controversial findings, which are the first to suggest such a high rate of malformations, come amid concern about the aggressive marketing and growing use of IVF in countries such as the US.

No one knovos whether the defects are linked to the factors that make couples infertile in the first place, or to aspects of IVF, or to both. If IVF itself is responsible, then clinics that push it on couples who may not need it are creating avoidable health risks, warns Allen Mitchell of Boston University School of Public Health in an editorial accompanying the study.

But even with the increased risk, a couple who conceive after IVF or intracytoplasmic sperm injection (ICSI) still have over a 90 per cent chance of having a healthy baby, stresses epidemiologist Jennifer Kurinczuk of the University of Leicester, a member of the team that carried out the research. And many defects can be surgically corrected.

"This level of risk will be acceptable to some," Kurinczuk says, but adding that infertility clinics should spell out these risks to their clients. "People considering IVF have to be aware of this and take it into account in their decisions." Together with colleagues at the University of Western Australia and other institutes in Perth, she examined records of pregnancies, deliveries and birth defects for babies conceived after infertility treatment in Western Australia between 1993 and 1997. Of the 837 IVF babies, 9 per cent had major defects, such as a hole in the heart or a cleft palate. For the 301 babies conceived by ICSI, the figure was 8.6 per cent. By contrast, only 4.2 per cent of the 4000 naturally conceived babies had major defects. Babies conceived artificially were also more likely to have more than one defect.

Other studies have not shown an increased risk. One Dutch study found birth defects in only 3 per cent of ICSI babies, for example. But Kurinczuk says the data her team used is more complete because, unusually, Western Australia requires all IVF procedures and birth defects to be registered.

Another difference is that many earlier studies used narrower definitions of birth defects, such as those "that cause functional impairment or require corrective surgery". Kurinczuk's team believe such definitions are too narrow. For example, being born with one kidney doesn't cause problems in children and cannot be corrected, but could cause problems in later life. But Robert Winston, a leading IVF researcher at Imperial College, London, warns that the study relied on the small population of Western Australia, which might not be representative. "The results should be interpreted cautiously." Phyllida Brown More at: The New England Journal of Medicine (voi 346, p 7251

New genetic spanner in the works

THE human genome may be almost completely sequenced, but it's still throwing up a few surprises. Italian researchers have discovered a new type of mutation that could cause a wide variety of diseases.

"No one could have predicted this phenomenon by computer or any analysis," says Francisco Baralle of the International Centre for Genetic Engineering and Biotechnology in Trieste, whose team made the discovery. "it has really changed our thinking."

To create a protein, cells make an RNA copy of the instructions encoded in DNA, and then use this to make the protein. But before these RNA blueprints can be used, "junk" sections that don't code for any part of the protein have to be removed. These so-called introns are spliced out by a complex molecular machine.

Genetic mutations in the gene being spliced can disrupt the process, with disastrous effects. But all the mutations known to do this lie either within the coding sections or at their edges. The rest of the introns themselves weren't thought to affect the process. At least, not until Baralle and his colleagues started studying a splicing defect in a gene called ATM. This mutation affects the brain and immune system, and also predisposes people to cancer.

To their surprise, the defect lay in the centre of an intron, where four "letters", or nucleotides, had been deleted. The mutation stops the splicing machinery from binding to the intron, which somehow causes the intron to be included in the final RNA.

The work reveals another level of complexity in the splicing machinery, says James Manley, a splicing expert at Columbia University in New York. "I think we will see these kinds of mutations more and more as we look more carefully," he says. Philip Cohen More at: Nature Genetics (DOI: 10.1038/ng8581

Cycles of Creation
WHAT happened before the big bang? If some physicists are to be believed, the question is about as meaningless as asking what is north of the North Pole. But others don't give up so easily.

According to two cosmologists, before the big bang there was another big bang. And, before that, another. "If we're right," says Neil Turok of the University of Cambridge, "the big bang is but one in an infinite series of big bangs stretching back into the eternal past." And into the eternal future.

What Turok and his colleague Paul Steinhardt of Princeton University are advocating is a new version of an idea that dates back to the 1920s. Back then the Russian physicist Aleksandr Friedmann, the father of the big bang idea, realised that if the gravity of all the matter in the Universe is powerful enough, it could stop the expansion of the cosmos and turn it around. The Universe would then carry on contracting down to a "big crunch". If both expanding and re-collapsing universes are permitted, it's a simple step to imagine the one changing seamlessly into the other. From the big crunch the Universe would bounce or rebound in a new big bang and the whole cycle would begin again.

It was a popular idea until the 1960s, when Roger Penrose and Stephen Hawking scuppered it. Using Einstein's general theory of relativity, which explains gravity as a warp in space-time, they showed that the big bang must have started in a singularity. A singularity is a point of infinite density and temperature, and it's a big problem for anyone taking a hard look at the physics of the big bang. That's because when everything in your equations goes to infinity, the equations are meaningless. Physics breaks down.

That doesn't rule out a cyclic Universe. But the singularity is like an opaque curtain, preventing a view through the big bang to earlier times. With the singularity in the way, it makes no sense to talk about any continuous existence. If the Universe passes through a singularity, everything gets scrambled in the breakdown of physics. Nothing in the new universe can be affected by what happened before, so the previous cycle might as well not have existed. This was very discouraging, and people abandoned the idea of a cyclic Universe.

Its rebirth has come about because physicists are now convinced that Einstein's theory of gravity breaks down at the big bang. It's all because of quantum mechanics, which seems to impose a fundamental fuzziness on things. Quantum theory is usually applied to particles of matter, but many physicists think it must affect space-time too. The implication, they say, is that nothing can collapse to a point. Instead there is a minimum size for anything. The Universe may once have been pretty amazingly small, but it wasn't infinitesimal, so its temperature and density weren't infinite. "The Universe may not, after all, have begun in a singularity," says Turok.

Over the past decade or so, this idea of space-time fuzziness has encouraged some physicists to think about what happened before the big bang. But on its own, it doesn't prove there was anything, or give any hints about what that was.

Then last year, Turok and Steinhardt came up with the first part of their new theory. It builds on what are called braneworld scenarios, an outgrowth of the idea that extra dimensions in space are needed to explain the fundamental forces of nature. To explain why we experience only four of these dimensions, physicists have come up with the peculiar idea that the matter and non-gravitational forces of our Universe are stuck firmly to a four-dimensional island, or "brane", floating within a higherdimensional space. Whereas most of the extra space dimensions are supposed to be rolled up much smaller than an atom, it may be that one of them is relatively large, and we simply don't see it because it is the exclusive realm of gravity (New Scientist, 29 September 2001, p 26). "The brane-world scenario suggests a possible explanation for the big bang," says Turok. Branes have their own mass, so a moving brane has an enormous amount of kinetic energy. And if our brane collided with another brane, this kinetic energy would be liberated, he thinks. "This could have created the fireball of the big bang and ultimately all the matter we see in today's galaxies and stars".

Turok and Steinhardt, who developed this idea with Justin Khoury of Princeton University and Burt Ovrut of the University of Pennsylvania, call it the "ekpyrotic" universe, from the Greek for "born out of fire". They have thought through several colliding-brane scenarios, some involving three branes. But what they've ended up with is a relatively simple scenario, in which two four-dimensional branes approach each other along a fifth dimension. Turok and his colleagues call them "boundary branes" because they form the ultimate boundaries of the Universe.

"What we have done is explore what would happen if one brane passes through the other," he says. They found that the kinetic energy of the colliding branes is converted into heat energy within the branes when they collide with each other, effectively conjuring real particles out of the vacuum. What's more, it naturally produces a Universe that is smooth on the largest scales, but has small lumps and bumps in it to turn into galaxies and galaxy clusters.

In this basic model, there's still no cycle. just a phase of approaching, empty branes before the big bang. Then Steinhardt and Turok asked themselves, what could pull the branes together before their collision? That something can only be the vacuum in between them, says Turok-because there's nothing else there. The vacuum, as it turns out, changes everything. "The vacuum is like a spring between the plates, or branes," says Turok. Within our Universe it appears to be generating a repulsive force-the so-called cosmological constant-which is driving apart the galaxies. An attractive force would seem to be incompatible with that. But it turns out that even while there is a repulsion along the space dimensions inside each brane, there can also be an attraction between the branes along the fifth dimension.

Turok's team is considering a number of possible mechanisms that might be behind this force. One suggestion is that there is a charge imbalance between the two branes that creates an attractive force between them. "We don't have a complete theory in which this could be calculated," Turok savs. "Our scenario is more of a guide as to how things could work." He believes that today, the spring is still being stretched, but in the far future it will reach its maximum extension. Once that happens, the branes will begin to accelerate towards each other until they collide again.

So in the new picture, the oscillation occurs only along the fifth dimension. lt happens like this: two branes are pulled together by the vacuum, and collide. Inside both branes a huge amount of energy is released, and the branes expand (if you can imagine an infinite rubber sheet being stretched out, it's a little like that). We brane-bound creatures call this event the big bang. As the branes expand and cool, matter and galaxies form. The galaxies drift apart and age. After a while, the gently repulsive vacuum inside the branes makes this expansion accelerate, so the galaxies fly apart faster still. The end looks bleak. But meanwhile the two branes have moved apart and then been pulled back together by the attractive vacuum in between them. They rush towards a collision once more, and a new big bang overwhelms both universes.

So from the perspective of someone stuck on the brane, space-time just keeps on expanding, though the expansion is given repeated pushes by successive bangs-that is, brane collisions. In other words, from the off-brane perspective, we have something more like the traditional cyclic universe, yo-yoing back and forth. Meanwhile, from the brane perspective, we have an altogether different kind of cycle in an eternally expanding Universe.

This overcomes another big problem with the old-style cyclic universe. In each cycle, stars radiate heat into space, but these cyclic models involve closed universes, so each bang is hotter than its predecessor. Looking backwards in time, then, the cycles get progressively cooler. The inescapable conclusion is that the cycles must have begun at some time in the past. 'But simply pushing the origin of the Universe back before the big bang is not very aesthetically pleasing," says Turok. "This is another reason why the cyclic universe was seen as unsatisfactory."

The new cyclic universe avoids this problem. After the branes have passed through each other, the spring of the vacuum is in compression and causes the space of the branes to expand for a long time. That dilutes the heat from stars so that the patch

of space that experiences each new bang has essentially the same temperature as the previous cycle. Consequently, all cycles are the same and the universe can have oscillated for ever. "Such a universe is more aesthetically pleasing than a big bang universe since the question of what happened before is no longer a nagging problem,' says Turok. "The Universe has been around for ever. There was no beginning."

Stars, galaxies and life may therefore have existed in previous cycles of the Universe. But, if the cycles are all identical, wouldn't such endless repetition be mind-numbingly dull? Turok and Steinhardt think not, because random events will change the details each time. You won't get the same galaxies, planets and people each cycle. "Just because the cycles repeat does not mean the events in each cycle are identical," says Turok. More speculatively, he points out that the extra rolled-up dimensions might vary their sizes between cycles. The significance of this is that the fundamental forces are suspected to be manifestations of the sizes of these extra dimensions. "The laws of physics could change from cycle to cycle," says Turok.

If the physical laws can change, they might be driven ever closer to some particular set, what physicists call an attractor. 'If we are lucky, we might find that the sizes of the extra dimensions home in on particular values," he says. "We might then finally have an explanation for, say, the mass of the electron." Obviously, both Turok and Steinhardt are excited by all these possibilities. Reactions from their colleagues are more mixed. 'At the moment I have an open mind on the ekpyrotic universe and its latest oscillating version," says Tom Kibble of Imperial College in London. "There is no doubt an element of hype here, but I think they are right to be excited."

Their most outspoken opponent is Andrei Linde of Stanford University. 'This is mostly hype," he says. He thinks the whole model is unnecessarily complicated, like the epicycles that medieval astronomers used to describe the orbits of the planets in our Solar System. But if Steinhardt and Turok are right after all, the future is less bleak and more dangerous than we have been told. Some cosmologists suggest that, because the galaxies are now accelerating apart, the future holds nothing but an ever emptier, cooler Universe. Now we have an alternative to look forward to: an almighty surprise, one day, when we and our fellow universe come together and collide once more in a spectacular finale. And who knows what will emerge from the fire?

Further reading: "The ekpyrotic universe: colliding branes and the origin of the hot big bang" by Justin Khoury, Burt Ovrut, Paul Steinhardt and Neil Turok, (www.arxiv.org/abs/hep-th/0103239) "From big crunch to big bang" by Justin Khoury, Burt Ovrut, Nathan Seiberg, Paul Steinhardt and Neit Turok (www.arxiv.org/abs/hep-th/0108187) Paul Steinhardt's website is at http:Hfeynman.princeton.edu/-steinh Neil Turok's website is at www.damtp.cam.ac.uk/user/ngtlOOO

Baptisms of fire

For 20 years, cosmology has been dominated by one theory that seems to explain all sorts of features of our Universe. The theory, called inflation, postulates a super-fast expansion in the Universe's first split second. Now it has a rival: Neil Turok and Paul Steinhardt's ekpyrotic model, the idea that the big bang was caused by two colliding universes. Before inflation came'along, nobody could explain why far-flung parts of today's Universe are at roughly the same temperature. This was a puzzle, because in the simple big bang model these regions would never have been close enough to exchange light signals, so there would have been no chance for heat to flow between them and even out the temperatures. The inflation theory is based on the idea that the Universe we see now came from a tiny region of the big bang. This region is so small that all parts of it could once have been in contact. In the ekpyrotic universe, this uniformity is explained in a similar way. It suggests the huge energy liberated in the collision generates a super-fast expansion just like inflation. Both theories can also produce the seeds of galaxies. In inflation, quantum fluctuations produce some slightly denser regions, which are magnifled by the violent expansion of inflation. In the ekpyrotic universe, the quantum fluctuations occur on the brane's surface as little hummocks that are tugged on and magnified by the gravity of the approaching brane. "it is possible to reproduce inflation's greatest successes with a non-inflationary mechanism," says Steinhardt. And according to Turok, the ekpyrotic universe does more. For instance, it provides a far more satisfactory framework for the kind of dark energy in the Universe that is pushing the galaxies apart. This vacuum energy is an integral part of ekpyrotic cosmology, and is required to bring the branes together and cause the big bang. In other cosmologies it just has to be conjured out of nothing. "if the basic components hold true then I believe that we have finally devised a model that is more compelling than inflation, something I would never have thought to witness, let alone take part in," says Steinhardt. This is praise indeed since Steinhardt was one of the founding fathers of the theory of inflation. Crucially, the ekpyrotic universe makes a prediction that inflation does not. And it's a prediction that could be checked in the near future. Inflation magnifies all spacetime fluctuations, so the Universe today should be awash in a sea of primordial gravity waves. These gravity waves should affect the temperature variations of the cosmic background radiation. The effect is subtle but might be detectable by the European Space Agency's Planck space probe, due for launch in 2006. The ekpyrotic universe predicts no such gravity waves, so if Planck and Planck's successors see none, it will be some support for the idea. A sign, perhaps, that the Universe truly is ruled by an endless cycle.

Smoking gun

In the early 1960s a team led by Robert Dicke and Jim Peebles of Princeton University predicted that if the Universe is oscillating, it should be aglow with leftover heat radiation. That's because if eactr cycle is to sta(t out the same, something must destroy the heavy atoms built up inside stars in the previous cycle. In effect, there must be something wiping the slate clean-and that could only be heat. Just such a relic, the cosmic microwave background radiation, was discovered soon afterwards. Dicke's team was beaten to the discovery by Amo Penzias and Robert Wilson, two a&ronomers at Bell Labs in New Jersey, who for a while thought they'd pic " kbd up the faint microwave glow of pigeon droppings on their radio telescope. But it turned out that you don't need a cycling universe to explain it, only some kind of big bang. And ironically, Wilson was a supporter of the steady-state theory, in which the Universe had been in existence for ever. So for at least two years after their serendipitous discovery, neither Penzias nor Wilson publicly admitted what they had found was the smoking gun of the big bang.

LIFTING THE CURSE

A BUNCH OF DOCTORS HAVE DECIDED THAT PERIODS ARENT HEALTHY AND WANT TO BANISH THEM FOR GOOD. SHOULD WE BE APPALLED OR DELIGHTED, ASKS SYLVIA PAGAN WESTPHAL

IF YOU'RE a woman, here's a tempting offer: stop having your periods now. Renounce the cramps, the bloating, the migraines, the moodiness and discomfort that take over your life once a month. Use your brain for something other that deciding between light and super-absorbent, deodorant or unscented. And best of all, feel good about it, because it's actually better for your health. Sounds too good to be true? Perhaps. But that's the controversial proposal made by a growing number of doctors who believe there is no medical reason for women to have reg ular menstrual cycles. "It is a needless loss of blood," says Brazilian reproductive biologist Elsimar Coutinho in his book Is Menstruation Obsolete? In fact, monthly periods could even be detrimental to women's health. And so the plan is to get rid of them. In principle, that's quite simple. Taking contra ceptive hormones continuously, either in the form of a pill, an injection or an implant, will stop menstruation for months or even years at a time. Those methods are economical and broadly available. Indeed, millions of women using contraceptives like Depo-Provera (DMPA) know at first hand that one of the perks can be no periods.

But here's the twist-Coutinho and likeminded scientists are pushing for a change in thinking. They'd like to see contraceptives given continuously not just for birth control, but as a means of suppressing periods to improve a woman's health and quality of life.

The first product to embrace this new attitude will soon hit the market in the form of Seasonale. It is identical to the good-old birth control pill, only packaged differently. The "regular" pill, made with synthetic versions of oestrogen and progesterone, is designed to be taken for 21 days in a row. The steady hormone levels fool your body into thinking you're pregnant, and so suppress ovulation. After this there is a week of either placebo pills or no pills, when women have their periods-the bleed is the body's response to the sharp drop in hormone intake. But with Seasonale you take placebo pills only at the end of the third month, meaning just four periods a year.

Even though Seasonale is made of the same hormones as the regular pill, its makers have had to design clinical trials to prove that taking those hormones continuously is safe and effective. Phase Ill clinical trials are under way, and if the US Food and Drug Administration gives its approval, by early 2003 Seasonale will be the first contraceptive specifically marketed to suppress women's periods for several months. "Once patients and physicians understand the benefits, this is going to be the way to take the pill," says Patricia Sulak of the department of Obstetrics and Gynecology at Texas A&M University. According to Sulak, who is not shy about admitting that her career goal is "to eliminate monthly periods", some of the best evidence that incessant menstruation is not what nature intended comes from our ancestors. Year after year of regular periods was not the norm for women until recently. "Ordinarily the pattern has been for a woman to be pregnant and lactating," says Sheldon Segal of the Population Council, and coauthor of Coutinho's book. Studies of contemporary hunter-gatherer societies suggest that women in prehistoric times had about 160 periods in their lifetime, compared with an average of 450 for women today. Better nutrition and higher standards of health in many countries mean women start their periods much earlier-at age 10 or 12-and reach menopause later. Also, these days it's common to delay childbearing until the late twenties, or even later, and the average number of children per woman is much lower. Thus, women now spend most of their reproductive lives menstruating every month, with few breaks for pregnancy or breastfeeding in between. Not only was menstruation rare for our ancestors, but it's actually an unusual event in the rest of the animal kingdom too. Only a few species of monkey, bats and shrews seem to menstruate. Clearly, shedding uterine tissue at the end of a fertile cycle is not nature's favourite female design. At the very least, incessant menstruation is inconvenient, and for many women the distress goes deeper than that: anaemia, migraines, cramps, fatigue and mood swings are a few of the symptoms commonly associated with lieriods. Most women put up with them as natural manifestations of the Tnonthly event, but Charlotte Ellertson of the PoiMlation Council in Mexico begs to differ. She argues that the symptoms often incapacitate women and affect their productivity. "This is surely an anomaly in medicine," states Ellertson in a provocative essay published in the medical journal The Lancet. "There can be no other disease or condition that affects so many people on such a regular basis ... which is not prioritised in some way by health professionals or policy makers."

But perhaps more importantly, repeated menstruation has been linked to a higher incidence of serious illness. Endometriosis, a condition that results when uterine tissue lodges inside the body cavity causing terrible abdominal pain during menstruation, has become more prevalent in many countries as women have begun to experience more menstrual periods, say Coutinho and Segal in their book. Also, it is now clear that the prevalence of reproductive diseases like ovarian cancer is closely linked to the number of periods in a woman's lifetime. Several studies show, for example, that women who've never had children, and thus have had no breaks from ovulation, have a higher risk of developing reproductive cancers. One theory is that the constant growing and re-building of tissue in the uterus predisposes a woman to cancer, another is that prolonged exposure to cycling hormones somehow triggers it. Either way, the link between lots of periods and a higher risk of cancers seems well established. But ask women if they'd like to get rid of their periods, and the answers will be visceral, passionate and conflicting. Suppressing menstruation goes against the hard-wired notion that the monthly period is one of the key hallmarks of womanhood. It has always had a special, mythical role in women's lives-it is curse and blessing, pride and taboo.

Several large studies by the World Health Organization and other institutions reveal that not all cultures are equally receptive to suppressing menstruation. A recent survey of women in seven countries showed that the majority did not want to modify their periods, let alone eliminate them altogether. In fact, such an outcome was a great source of concern for women considering long acting contraceptives like DMPA or Norplant. Women in India and Thailand, for example, opposed the idea because they believe menstruation is good for their health and their looks.

In Western societies, women seem more open to giving up their periods, perhaps because of a stronger focus on lifestyle and career. In a recent Dutch study based on interviews with over 300 women, about 70 per cent of those between 15 and 50 would rather have their periods less than once a month, and of these the majority would prefer periods either every three months or never. Several small studies in other countries, including Britain and Sweden, produced similar results. Also, from a less scientific but more lively survey, hundreds of women have posted replies to the question "Would you stop menstruating if you could?" at the online Museum of Menstruation. This gem of a website is a virtual repository for everything you ever wanted to know about women's periods. "I'd say it's five to one in favour of stopping," says site founder Harry Finley.

But it's obvious that even those seriously considering the change are deeply torn about stopping periods merely for convenience. There is indeed a cultural bias against stopping periods without a good reason. In fact, this is the motive behind the original 21 -day regime for the pill. When a woman takes the pill, the hormones prevent ovulation, but also most of the usual tissue growth that happens in the uterus as it prepares for implantation of an egg. Then, once placebo pills are started, or the gap week is reached, the uterine tissue reacts to the drop in hormones by breaking down, even though there is not much tissue to shed. The bleed actually has little biological resemblance to a real period.

So why take a break from the hormones at all? Because the pill's creators figured that women (and the church, for that matter) would feel more comfortable with a schedule that seemed to mimic the real thing. "That's why the pill was so successful,' says Sulak. "They could have put 36 or 42 pills in the pack, but they chose 21 because they knew." In fact, the 'period" is, in a way, as artificial as the hormones themselves. Sulak argues that it's not any less natural to skip those placebo pills and continue to take the hormones uninterrupted. There is one fundamental problem, though, with the available hormones. To be sure, they are very effective contraceptives. But for reasons that still puzzle researchers, women who take these hormones continuously often get unpredictable bleeding, or spotting. With DMPA or Norplant, it's common for most women to have irregular bleeding for a few months, until their body gets used to the schedule. And it's one of the most common reasons women give up on long-acting contraceptives. Freedolph Anderson of Eastern Virginia Medical School, who is overseeing the clinical trials with Seasonale, says that taking the pill at the same time every day is proving crucial to stopping breakthrough bleeding.

A contraceptive called Mirena, which releases the same hormone as Norplant but via an intrauterine device, apparently reduces intermittent bleeding quite successfully. Also, a new generation of compounds, called anti-progestins, seem to be excellent contraceptives and effectively stop spotting. Anti-progestins work differently from conventional hormone contraceptives by blocking the action of the body's own progesterone, which is vital for a viable pregnancy. Doing this prevents both ovulation and much of the build-up of uterine tissue. But an additional effect is the temporary atrophy of blood vessels in the region, which seems to prevent spotting quite efficiently. But even if problems with spotting are resolved, taking the no-periods trend into the mainstream will require significant effort. For example, it will be hard to convince some women to let go of the comforting monthly bleed that reassures them they are not pregnant. Experts argue that if women follow the rules, it is very unlikely that they will get pregnant, since prolonged use of contraceptives leads to a uterus that, as long as they are still taking the hormones, increasingly cannot support a pregnancy. Conversely, women will want to be reassured that fertility will return shortly after they stop taking the hormones-which studies so far show is indeed the case. In fact, according to a titillating but very preliminary theory, the treatment might even prolong fertility if we can find the right compound to suppress ovulation at its earliest stages. "So it might be that if you retain the eggs, the quality pater on] might be better. The window of fertility could be held back," says Roger Gosden, scientific director of the Jones Institute at Eastern Virginia Medical School. There are a few candidates for such a "career pill" already. But at the moment, Seasonale will not offer such a perk-it does block ovulation, but the eggs still begin to mature in the ovary, and so wither away and die as they would during a normal menstrual cycle.

Also, women are unlikely to accept the shift unless they are convinced it's safe. There's a solid case for the long-term safety of injectable progestin-based contraceptives such as Depo-Provera for most women. But there are isolated reports of serious adverse effects and unpleasant side effects like a tendency to gain weight. And while oral contraceptives can significantly reduce the risk of reproductive cancers, there are no studies of the long-term effects of taking oral contraceptives without the placebo break. After all, the non-stop schedule means exposing women to the hormones for 25 per cent longer. Oestrogen in the pill has been associated with a slightly higher risk of stroke, especially in smokers or women with conditions like diabetes and hypertension. So doctors will have to look at how the extra exposure might affect health. "We don't have all the evidence yet for doing this for years on end, but most physicians would agree that doing it for months at a time has been perfectly safe," says Ellertson. But reearcher Lawrence M. Nelson from the National Institutes of Health worries about branding menstruation as unimportant. "We think the menstrual cycle doesn't get the respect it deserves as a sign of good health," he says. He believes that the cycle is like the body's thermostat, a sensor of hormonal balance and general well being. By giving women contraceptives, serious conditions like ovarian dysfunction, which causes infertility, could be masked and go undiagnosed for years. Taking the hormones, argues Nelson, would "remove the vital sign,' which is the period.

In fact, Ellertson says that some feminist groups have reacted negatively to arguments in favour of suppressing women's periods. They complain that doctors are making the menstrual cycle look like a sickness that needs to be "cured". And that the whole argument about what's normal is pointless-it's akin to saying that our ancestors were hungry more often, and therefore hunger should be the "normal" state. In the end, no amount of advertising or pressure from doctors will make women adopt a concept they don't feel comfortable with. But Anderson is convinced. "Women will ask for this."

Further reading: Is Menstruation Obsolete? by Elsimar M. Coutinho and Slyeldon J. Segal, Oxford University Press, 1999 The Museum of Menstruation is at www.mum.org