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No escape for alien genes NS 10 may 2003

Geneguard: A technique that locks in added genes may benefit farmers in the developing world

ANDY COGHLAN

POOR farmers could soon be growing genetically modified plants from home-grown seeds. The plants have been designed to produce fertile seed that carry desirable new traits, but will be incapable of spreading their alien genes into the environment. This is a crucial feature that could herald a new era in GM crops. Environmentalists have long warned about the dangers of GM plants transmitting new traits to other plants. Genes intended to make crop plants resistant to weedkillers have already spread to other crops on farms, notably in Canada. To avoid this, biotech companies proposed making their GM crops sterile, using so-called "terminator" technology. But the idea simply raised another problem: poorer farmers would no longer be able to save seeds from one harvest to sow the following year. The resulting outcry forced biotech companies to abandon terminator technology. Now it is back on the agenda ir the shape of a tobacco plant that can self-pollinate and produce C viable seeds but cannot reproduc with any other plants. "It's a trick to keep a seed line genetically pure yet stop the GM trait escaping," says johann Schernthaner of the Canadian team that devised the patented system, dubbed Geneguard. The work was done at the Eastern Cereal and Oilseed Research Centre in Ottawa, part of Canada's agriculture ministry. The modified tobacco contains two extra genes in addition to those added to provide a beneficial trait such as disease resistance. Both originate in bacteria. The first, from the soil-dwelling Agrobacterium tumefaciens, inhibits seed germination. This gene is directly linked to the DNA that confers the beneficial trait, so any seeds with just these added genes cannot germinate. The second bacterial gene, from E. coli, blocks the action of the first one. "Its protein simply sits on the first gene and prevents it working," says Schernthaner- With both genes present, germination proceeds normally and the seeds can grow into mature GM plants and self-pollinate, generation after generation. "As long as the plant fertilises itself, it can be maintained forever," he says. The key feature of Geneguard is that the two bacterial genes separate when the plant makes pollen. This means that if the GM pollen fertilises a wild plant or conventional tobacco, any resulting seeds with the disease- resistance trait will also have the germination blocker. They may inherit the second bacterial gene instead, but by itself this is innocuous (Proceedings of the National Academy ofsciences, DOI: 10-1073/pnas-1036833100). The researchers have not yet perfected the Geneguard system, because they cannot guarantee that the beneficial trait will not escape. The two bacterial genes have to be inserted separately into the chromosomes of two parent plants, which are then bred together to produce offspring carrying both genes. To ensure that the genes separate during pollen formation in the GM tobacco, they must be inserted into exactly the same position on both parent plants'chromosomes. The Canadian team has not yet achieved this. But Schernthaner points out that it maybe possible through a technique called site-specific insertion. Other agriculture ministry researchers based in Saskatoon, Saskatchewan, are trying to use the technology in oilseed rape. But ETC Group, a lobby organisation critical of GM technology based in Winnipeg, Manitoba, is not convinced of Geneguard's benefits. "It's bad news for farmers," says ETC's research director, Hope Shand. Poor farmers will not be able to breed their own varieties from their saved seeds, she points out. "If this technique works, it might reduce industry's risk from GM contamination," she concedes. But she thinks the price is too high: "The loss of breeding capacity is an unacceptable trade- off." But Schernthaner says poor farmers seldom have the means to develop their own varieties.

Curioser and curioser Yakir Aharonov believes we can now see inside the weird quantum world

The idea that the quantum world is disrupted by those who observe it has frustrated researchers for almost 80 years. Goodbye to all that, says Michael Brooks

WE HAVE always been aware that quantum stuff moves in mysterious ways. A quantum particle such as an electron can spin clockwise and anticlockwise at the same time, for example, or exist simultaneously in two places. We've also known that these strange "superpositions" are extremely fragile. Indeed, it is a tenet of quantum theory that as soon as anyone tries to observe a superposition, it collapses back to some kind of normality. Make a measurement of, say, an electron spinning both ways at once and the electron appears to have just one spin.

That is why Schrödinger's famous cat can only be both alive and dead at the same time in its box so long as no one looks inside. Lifting the lid forces the cat to either live or die. And so this mysterious quantum world has remained impossible to explore. Until now, that is.

Yakir Aharonov, an influential physicist at Tel Aviv University and the University of South Carolina, believes he has discovered a way to observe the quantum world without destroying superpositions. This is a stunning claim and flies in the face of 80 years of teaching about quantum theory. But Aharonov says a technique he has invented, called "weak measurement", shows that looking at something doesn't have to change it. "Weak measurement finds what is there without disturbing it," he says.

Although Aharonov has been working on weak measurement for 15 years, his confidence has recently grown enormously. Last year he published a paper showing that weak measurement can give us new insight into a previously inexplicable paradox in quantum mechanics ( Physics Letters A , vol 301, p 130). The result of this work is "strange and surprising", Aharonov says, but shows quantum theory to be logical and self-consistent. Weak measurement, he believes, will be the tool that finally opens up the weirdness of quantum theory for inspection.

The paradox in question is a thought experiment described in 1992 by Lucien Hardy, then at the University of Oxford, which shows how quantum theory makes a nonsense of the interaction between matter and anti-matter. First Hardy considered a Mach-Zender interferometer, an instrument in which a quantum particle hits a half-silvered mirror. This sends it into a superposition of states, in that it travels down two separate arms at once.

The interferometer later reunites the two paths, although what happens then depends on what happened en route. The arms of the interferometer meet at another half-silvered mirror, which is arranged so that if the particle has had an undisturbed journey - that is, it doesn't encounter any other particles or fields - it is collected in a detector "C". But if something disturbs the particle while it is on its way through the interferometer, it may arrive at a second detector, "D".

Hardy imagined two such interferometers positioned so that one arm of the first overlaps with one arm of the second (see Diagram) . Then he imagined sending a positron - the antiparticle of an electron - through one interferometer, and an electron through the other at the same time. If the two particles travel along the overlapping arms they should meet in an "annihilation region" and destroy one another.

Hardy showed that something much stranger happens: in rare cases, quantum theory predicts that both D detectors could click simultaneously. Somehow both particle and antiparticle could disturb, yet fail to annihilate, each other in the overlapping arms.

The situation arises because quantum theory deals with probabilities amassed from the multiple existences of particles. Since the particles can simultaneously be in and not in the overlapping arms, the probabilistic nature of quantum theory allows an improbable - yet possible - outcome that makes no sense. This is Hardy's paradox.

In the decade since Hardy described it, people have "resolved" the paradox by saying that the thought experiment doesn't correspond to any possible real experiment, and is therefore meaningless. The only way to find out what really happens to the particles in the experiment would be to measure their routes, rather than simply inferring them from the final result. But as soon as a particle detector is placed in any of the paths, standard quantum theory says the particles will be disturbed, guaranteeing that the D detectors will fire. So you can no longer infer the particles' positions: the paradox is lost.

"The general attitude is 'since the paradox disappears when measurements are performed, the whole paradox is a red herring and doesn't deserve much attention'," says Sandu Popescu of the University of Bristol and Hewlett-Packard Labs, Bristol. But Popescu and Aharonov think otherwise. Working with Tel Aviv Unversity's Benni Rezni, Alonso Botero of Texas A&M University, and Jeff Tollaksen of Boston University, they have devised a modified version of Hardy's thought experiment that could be performed in a lab. By their calculations, the paradox will still exist, but because the experiment can actually be done, it means the paradox cannot be dismissed as abstract reasoning: it must be an objective truth of quantum theory.

The "weak measurement" technique they propose exploits quantum uncertainty - the fact that in any quantum system there is always an intrinsic uncertainty about properties such as a particle's position and energy. Aharonov's quantum detector is so weakly linked to the experiment that any measurement moves the detector's "pointer" by less than the level of uncertainty. In return, the detector has an imperceptible impact on the experiment. Astonishingly, this means any superpositions are preserved.

There is a price to pay for these delicate readings, however: they are extraordinarily inaccurate. But while this might appear to make the whole process pointless, Aharonov has calculated that when repeated many times, the average of these measurements approximates to the true value of the thing being measured.

Imagine a set of scales designed to measure the weight of an electron. In a weak measurement, quantum uncertainty means that the position of the scales' pointer will always be uncertain by a small amount, and the size of that discrepancy will be larger than the weight of the electron. This makes it impossible to say for certain what an electron weighs. But if billions of electrons land one at a time on the scales, the average of all the measurements will reveal the weight.

Of course, if it is not clear that an electron is on the scales or not, taking an average of all the readings won't give a true indication of its weight. The average will be skewed to a lower value by the occasions when no electron was present. But Aharonov and Popescu get round this problem: they know which runs of the experiment make both D detectors click and so can choose which measurements to throw into their average, and which to ignore.

In their thought experiment, Aharonov and Popescu "post-select" the results: they focus on just the paradoxical incidents when both D detectors click. The weak measurements then build up a picture of what is going on, all without disturbing the system. The reward is a result that presents the paradox in a fully logical, self-consistent way.

The apparatus in their thought experiment includes an array of detectors that make one of two different types of weak measurement. One type counts the number of electrons or positrons that pass along each arm. This could be a gravitational field detector fixed strongly in place so the particle's presence transfers almost no momentum. The second weak measurement comes from "pair detectors" that can record an electron and a positron passing simultaneously past two separate points. These "pairs" might be measured by two boxes connected by a rigid spring - the attraction between a pair would slightly compress it. The exact methods are not as important as the fact that they could be physically performed in the lab. All these weak, inaccurate results are recorded only when both D detectors click, and the results are then averaged over many runs of the experiment.

With the mental apparatus assembled, the physicists "run" the experiment. The results are predictable - at least in quantum terms. First they calculate the number of electrons passing through the annihilation region every time both D detectors click. The average is 1. The number of positrons passing through the region is also 1. The same measurements made for the non-overlapping arms of the interferometer give 0. This is exactly what would be expected with both D detectors clicking: both particles must have been in the annihilation region for them to disturb each other. So why didn't they annihilate? Another calculation reveals a rather puzzling answer to this question. The pair detectors show that the number of electron-positron pairs in the annihilation region is 0.

Other pair detectors reveal even stranger results. One indicates the presence of an electron in the annihilation region at the same time as a positron travels down the non-overlapping arm. Another shows a positron in the annihilation region while an electron is in the non-overlapping arm.

So with weak measurements, the paradox remains: we have an electron and a positron disturbing each other in the annihilation zone, yet pair measurements tell us they were not there together, so could not have disturbed each other. But there's now an additional difficulty: the results imply that there are two pairs of particles in the apparatus at the same time. And we know that's not true. It seemed like a fundamental flaw - until, that is, Aharonov and Popescu looked at a final pair-measuring device in the non-overlapping arms of the interferometer. The reading there was -1. Somehow, there was a "negative presence".

Aharonov says that when he first saw the negative number come out of the pair measurement, he was rather taken aback. Nobody had seen anything like it before. "It looks impossible. But then I realised it was the only way to see it. It's beautiful."

What exactly a -1 result means is still up for grabs, but Aharonov and Popescu believe they have shown that there is a way to carry out experiments on the counter-intuitive predictions of quantum theory without destroying all the interesting results. A single quantum particle could have measurable effects on physical systems in two places at once, for instance. Indeed, Aharonov and Popescu say, when you get a look inside, quantum theory is even more bizarre than we thought. Quantum particles can assume far more complex identities than simply being in two places at once: pairs of particles are fundamentally different from single particles and they can assume a negative presence.

And the fact that weak measurements transform the paradox from a mere technicality into an unavoidable truth suggests that they could provide a springboard for new understanding in quantum mechanics. "It shows there are extraordinary things within ordinary quantum mechanics," Popescu says. The negative presence result might be just the tip of the iceberg: every paradox in quantum theory may simply be a manifestation of other strange behaviours of quantum objects that we have not yet detected - or even thought of. "Many of the well-known paradoxes of quantum mechanics have properties like this," Popescu says.

From thought to reality

Klaus Mølmer of Aarhus University in Denmark was initially sceptical about weak measurement, but his own examination of Aharonov and Popescu's work has convinced him it has to be taken seriously. He even thinks he knows how to demonstrate it in a real experiment. It could even be done now, since it exploits the same techniques that quantum computing researchers use (see "Paradox lost") .

Hardy, now at Ontario's Perimeter Institute, is also impressed by Aharonov and Popescu's work, but questions its meaning. "In spite of the consistency with which the apparatus gives these negative readings, it is quite a jump to infer that there really are a negative number of particles," he says. Instead, Hardy suggests, it might just be a form of error. But, he concedes, there is definitely a case to answer because the apparatus consistently gives the same error - a negative number of particles whenever both D detectors click. "This error is consistent with what might otherwise be regarded as some kind of naive reasoning about otherwise paradoxical situations."

While Hardy remains noncommittal about weak measurements, Popescu insists that there's nothing unusual about them. They are not a magic trick, and not even a convenient "interpretation" of quantum mechanics. "They are a particular type of measurement, and their results are just ordinary experimental results," he says. "Unusual experimental results, to be sure, but not fiction."

Aharonov admits that his ideas about weak measurements remain "widely unaccepted", but he's not cowed by that. Everyone will talk in terms of weak measurements in the future, he says; some are already learning the language.

Raymond Chiao of the University of California at Berkeley and Aephraim Steinberg of the University of Toronto, for example, are looking at weak measurement as a way to explain photon tunnelling. It is widely accepted that quantum objects such as atoms and photons can "tunnel" through barriers that they don't strictly have enough energy to get over. Experiments show that photons really can do this - and at speeds greater than the speed of light. Chiao and Steinberg, who performed the first experiments to demonstrate photon tunnelling, are exploring the idea that, since the photon's chances of accomplishing this feat are tiny for a wide barrier, their experiment might have been a post-selected weak measurement, allowing them to observe a strange quantum event that defies ordinary logic. It may involve negative energies or even negative time. They are exploring these possibilities in further experiments that use weak measurements.

Howard Wiseman of Griffith University in Queensland, Australia, also believes weak measurements can help shed light on strange quantum phenomena. In a forthcoming paper in Physics Letters A , Wiseman shows how weak measurement and negative presence can interpret double-slit interferometer experiments. Fire an electron at a pair of parallel slits and, if left undisturbed, the electron produces a pattern on a screen behind the slits that is created by interference between two electron states in superposition.

Some have suggested it might be possible to determine which slit the electron went through to find out what is really going on with the electron's simultaneous wave and particle existence. But this has generally been deemed impossible because any attempt to look at the electron gives it extra momentum, which affects the outcome and washes away the interference pattern. But Wiseman has shown that weak measurement reveals that such momenta can take on a negative value, giving a net momentum of 0 to the electron and letting researchers determine which slit the electron went through. It is, he says, possible to do this with existing technology.

Mølmer's experience with translating weak measurements into a real lab experiment makes him think that most of what has been done to date with quantum systems employs weak measurement - physicists just haven't realised it. He now believes weak measurements might even have practical repercussions. They could, for example, expose flaws in quantum cryptography, in which disturbance caused by measurement is supposed to prevent eavesdroppers decoding messages. "A weak measurement used by an eavesdropper could be an interesting strategy," Mølmer says.

Whatever the implications - and Popescu and Aharonov are sure they've only begun to scratch the surface - a new door has opened. Weak measurement should give us a view inside the processes of quantum mechanics that we once thought impossible. It has already uncovered a negative presence that we never knew existed, and there could be plenty more surprises waiting to be found.

Eventually, Aharonov believes, weak measurement may dispel all our present notions of the weirdness of the quantum world. Aharonov claims that when the Nobel laureate Richard Feynman famously pronounced that we can never truly comprehend quantum mechanics, he was "too hasty". "I think people will remove the mystery that Feynman said could never be removed," he says. "You should never say never."

PARADOX LOST

YAKIR AHARONOV has shown that In quantum wms, two contradictory things really can happen at once. His exploration of Hardy's paradox (see Graphic, opposite) using "weak measurement" Is more than an abstract thought experiment: with a twist, it can be done in the lab. Klaus Molmer of Aarhus University in Denmark suggests probing the locations of a pair of Ions instead of the electron and positron. First, cool the ions down to their lowest energy state and hit them with two carefully engineered laser pulses. This should send the ions into a superposition that Is analogous to the state of the electmn and positron passing through Hardy's experiment on their way to hitting the D detectors. In Molmer's version, the Ions move to positions they should never occupy. Molmer sets the ions up so that they will always fluoresce, except when they are in this pa,radoxical superposition. As soon as the fluorescence vanishes; he carries out a weak measurement on the ions' position using another laser - equivalentto measuringthe positions of the electrons and positrons in Hardy's experiment. The laser light forces the ions apart by less than the intrinsic quantum uncertainty in their position. Repeated many times, thi5 finy push is enough to expose the strange shift in the ions' position (Physics Letters A, vol 292, p 151). The centre of mass of the pair should lie somewhere between them. But the weak measurements show that, in the paradoxical quantum state, the ions'centre of mass lies outside this region. If the ions were at coordinates 0 and 1, the centre of mass Is at -1. "It's like you're weighing yourself and it shows -60 kg," Molmer says. it's not that weird, though, he insists. Quantum theory allows the particles to be considered also as waves, and the experiment simply reflects the destructive interference of those waves. Nevertheless, he believes it is a brilliant resolution. In a physical realisation of the Hardy paradox, you would exped all hell to break loose and everything to become nonsensical. But it doesn't.

The next IVF revolution.

We could be on the verge of creating children from artificial eggs and sperm made in a lab dish, if world on mice can be repeated with human cells

SYLVIA PAGAN WESTPHAL, BOSTON

THE mammalian egg, the cell that holds the secret to fertility, cloning and cell rejuvenation, has been created outside the body for the first time. And, New Scientist has learned, researchers are very close to creating sperm in a similar way. The feat was accomplished with cells originally derived from mouse embryos, but most experts see no reason why the technique would not work with human embryonic stem cells too. if human eggs and sperm created this way are healthy - and it is a big if -the implications for reproductive technology and regenerative medicine would be immense.

Most immediately, a cheap, limitless supply of human eggs would greatly accelerate research in keys fields such as infertility and therapeutic cloning. "It's terrific," says lose Cibelli of Michigan State University, the first scientist to publish details of attempts to clone human cells. "Eggs were one of those cell types we never thought we could produce." In the longer term, the applications might even include allowing infertile women or a pair of men to have their own children. The key step in the formation of eggs and sperm is a form of cell division called meiosis, which produces cells with one set of chromosomes instead of two. Fertilisation then creates an embryo with the full two sets.

There have been attempts to create artificial eggs or sperm by persuading normal cells to spit out one set of chromosomes (New ScientiSt, 22/29 December 2001, p 24), but embryos created from such cells never survive long. This failure involves imprinting, the process whereby chemical changes to DNA turn some genes on or off. For an embryo to develop normally, its genome must have the correct imprinting pattern, which forms as eggs and sperm cells mature. You cannot create an embryo merely by adding the set of chromosomes from one egg to those of another, because paternal chromosomes have a different pattern of imprinting from maternal ones.

The method used to create eggs from embryonic stem cells (ESCS) was astonishingly simple. Instead of searching for chemicals that coax ESCs into becoming eggs, as many have attempted, Hans Sch6ler's team at the University of Pennsylvania just let mouse ESCs grow at zL high density. In these conditions, some of the cells form floating aggregates most scientists would discard as useless debris. But team member Karin Hilbner instead placed the clumps in new dishes. "In four days they proliferated like crazy," says Sch6ler. The aggregates seem to behave like miniature ovarian follicles in which small cells nurture a bigger cell that forms an egg. Further studies by the team revealed that these egg-like cells form by meiosis, and switch on the same key genes as normal eggs as they develop. The follicle-like structures make hormones such as oestradiol in amounts that rise and fall on the same timescale as the menstrual cycle. Adding a hormone called gonadotrophin triggers the expulsion of the egg cell into the culture dish, mimicking ovulation (Science, DOI: 10.1126/science.lo83452). Intriguingly, eggs form from both female (XX) and male (XY) ESCs. That is because mammalian germ cells will go down the egg route unless signals produced by the testes tell the cells to become sperm. This is also why getting ESCs to turn into sperm is more complex. However, a team led by Toshiaki Noce at the Mitsubishi Kasei Institute of Life Sciences in Tokyo may already have succeeded. According to a document found by New Scientist, the team allowed male mouse ESCs to develop spontaneously into various different types of cell, and picked out those that had begun turning into germ cells. These cells do not develop far in culture, but when Noce's team transplanted them into testicular tissue he found after three months that they had undergone meiosis and formed what appeared to be normal sperm. Both teams have yet to perform the next, crucial step: fertilising the artificial eggs with normal sperm, or using the artificial sperm to fertilise normal eggs. Since Sch6ler's egg have a thinner outer layer and are more fragile than normal eggs, they could be harder to fertilise. The big question is whether the resulting embryos will have normal imprinting and develop into healthy baby mice. "There is always a possibility that the imprints would not be normal," says Azim Surani of Cambridge University. He points out that imprinting can be affected simply by growing cells in the lab. Even children born through normal IVF may have a higher risk of certain defects.

"The big question is whether the resulting embryos will have normal imprinting and develop into healthy baby mice"

"You could create lots of abnormalities," warns Surani. But if the animals are normal, the race will be on to create artificial human egg and sperm cells this way. It is likely to be much harder with human cells. Attempts to obtain human eggs simply by growing slices of ovarian tissue have failed, and the only mouse created from an egg obtained this way, dubbed Eggbert, was sickly and died young. it will also be slow: it takes up to six months for a human egg to mature. But if it can be done, the possibilities are astounding. In cloning, for instance, there are massive problems with imprinting. When a nucleus is transferred to an empty egg, chemicals in the egg seem to alter the imprinting, "reprogramming" the genome to ensure the right genes are expressed in the growing embryo. But the process is far from perfect, and many cloned embryos die or give rise to animals with major defects. The offspring of cloned animals, however, seem to be normal, prompting some cloning experts to suggest that the formation of eggs and sperm corrects any lingering imprinting defects. It might be possible to take an individual's cell, create ESCs from it by therapeutic cloning, and then derive healthy eggs or sperm from them for use in IVF (see below). The most obvious application would be to treat infertile women who cannot produce any eggs suitable for IVF, or men who cannot produce sperm. And because male ESCs can be turned into eggs as well as sperm, two men could both be biological parents of a child, with the help of a surrogate mother; two out of three of such children would be male. The technique would not allow two women to have children together, though, as female ECSs lack the Y chromosome, without which sperm cells appear unable to form. While it sounds far-fetched, the method would even allow "self- fertilisation" by a man. Such a child would not be an identical clone of its parent, as it would have lost some of his genetic diversity. Even more controversially, it might be possible to genetically engineer children by modifying ESCs in culture and then deriving and selecting sperm and eggs carrying the modifications. For now, the potential risks of the technology rule out such uses, Surani says. And Schbler agrees.

"The one thing I don't want is that the oocytes be used to make humans," he says. Yet while some countries have regulations that would prohibit the use of the technology, in the US and other countries there is far less control of IVF clinics. Now may be the time to consider the potential benefits and concerns, before experiments even begin with human cells. "It's always good to have these kinds of debates of potential ethical issues," says Surani.