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NS 14 sep 02
Asteroid threat is greater than ever'
Tracking dangerous asteroids is no longer enough, its time to make sure we can fend off any coming ourway
EUGENIE SAMUEL, WASHINGTON DC
THE world is unprepared for an asteroid strike, and we should be planning now to protect ourselves. That's the frightening conclusion of an intemational group of experts who met last week at a NASA workshop on the asteroid threat. After nearly five years of intensive surveys, researchers are caging for an urgent shift of emphasis. There is now an estimated i in 5 chance that an asteroid big enough to destroy a city wffl hit the Earth in the next loo years. Yet the long-term orbits of most dangerous asteroids are proving hard to pin down. "I feel a lot less safe today than I did," says Mike Belton, who worked on comet observations at the National Optical Astronomy Observatory in Tucson, Arizona, before founding NASA contractor Belton Space Exploration Initiatives, also in Tucson. So instead of just scanning the skies for asteroids on a collision course, many researchers are backing a $3 billion programma to develop ways to deflect an object found to be heading our way. Over the past five years, most researchers have been happy to not worry about how to protect ourselves unless we found a rock with our name on it. The LINEAR (Lincoln Near Earth Asteroid Research) telescopes in Socorro, New Mexico, and other optical surveys have so far logged more than half of the looo or so asteroids over 1 kflometre across which are in orbits that could cross Earth's (see Graphic). But although none so far is on target to collide with us, that view has changed, and the people thinking up schemes to deflect asteroids or blow them up are no longer fringe figures. One reason for the diange of heart is that the more we find out about the composition of asteroids, the more difficult the task of deflecting them appears. For example, follow-up radar images of asteroids found by LINEAR show that almost afl of them rotate more slowly than lo times per day. This cut-off suggests that what we thought of as rocks are actually rubble piles that would fly apart if they rotated any faster, Alan Harris of the German Aerospace Centre in Berlin told the workshop, held near Washington DC. Such objects would be extremely difficult to move or deflect in a predictable way. What's more, radar studies published earlier this year show that around i in 6 known asteroids are actually binary systems, malting them even harder to approach and land on than previously thought. Belton now fears that the knowledge required to intercept and deflect an asteroid could take centuries to collect. And it's not just the big ones we need to worry about. A growing concem is the large number of smaller asteroids, between 3oo and 1000 metres across, that are being detected by current surveys. These bodies are not being carefully tracked or studied because they are probably too small to cause a global catastrophe. But they could easily wipe out a city if they landed nearby. Researdiers now estimate there is a 1 in 5 chance of an asteroid in this size range hitting Earth in the next loo years. "That is precisely why I decided to change my life and get into asteroids," says Belton. . Worse, iVs becoming clear that we can't be sure about the orbits of these smaller asteroids, however carefully we track them. At the workshop, Duncan Steele of Salford University near Manchester showed how radiation pressure from the Sun can make smaller asteroids drift from their predicted orbit. Findings like this have convinced researchers that it's time to look into methods of dealing with dangerous asteroids. "We should pick a concrete goal of, say, moving an asteroid of 15o metres across by 5 to lo centimetres per second by 2015, and work up," says Ed Lu of NASA Johnson Space Center in Maryland. At the workshop, Belton outlined a 25-year strategy for this work that would cost $3 billion - a vast investment compared with the $4 million a year the US now spends on asteroid studies. Those with the money, however, are busy passing the buck. One obvious source of ftinding is NASA, but it is still focusing on basic science. Ed Weiler of NASA headquarters in Washington DC said the agency would not be responsible if an asteroid destroyed the Earth. "I can't take responsibility unless I have H-bombs in my desk," he says.
And Pete Worden of the US Air Force headquarters in Washington DC told the workshop that the US military will not be a major source of ftinding unless there is a clearer chain of command within the US government of who is responsible for defining asteroid risks. With no other intemational organisations spending significant amounts of money on asteroid deflection, the task of saving the planet may yet fall to private institutions or charities. For example, Apollo 9 astronaut Rusty Schweickart and Clark Chapman of Southwest Research Institute in Boulder, Colorado, are tired of waiting for funds to appear. They aim to use charitable funds to develop the technology needed to move an asteroid. "if you flnd someone with a few tens of millions of dollars and name the mission after them, maybe that's the way to go," says Erik Asphaug of the University of Califomia, Santa Cruz, who organised the workshop. If govemments won't stump up the cash to protect the planet, they won't get the credit either.
Engineering safer soya
THE protein that causes the vast majority of-allergic reactions to soybeans has been stripped out via genetic modification. lt is being cited as an example of how GM technology can make food safer for consumers rather than simply line the pockets of seed manufacturers. Soya allergy is most likely to affect children under rive, although a small percentage of adults are also allergic to soya. Afthough the allergy can be severe, it mostly shows up as hives, itchy skin and diarrhoea. More than haff of these allergic reactions are caused by one protein in soybeans, called P34. Researchers with the US Department of Agdcufture and biotechnology company Pioneer HI-Bred lntemational of Des Moines, Iowa, have now knocked out the P34 gene. And since last year soybeans without the protein have been grown in Hawaii. To eliminate the offendilog protein, the team used an established "gene silencing" technique called sense suppression. To do this, extra copies of the gene that codes for the P34 protein were spliced into the plant's DNA. Rather than increase production of the pmtein, this has the opposite effect. This is because the additional genes turn up production of messenger RNA that tells the cell to make the P34 pmtein. The plant evidently interprets this surge of RNA as a sign of viral infection, so it destroys all the RNA and eventually suppresses the genes that make it - induding the plant's original copy of the gene. The researchers found that knocking out P34 caused no changes to other proteins in the plants, which seemed to grow as well as natural varieties. Although no one knows what the protein's function is, it does not seem to be necessary fbr the plant's health. When blood serum taken from people allergic to soya was exposed to the modified beans, the scientists found no antibody response to the P34 pmtein, suggesting it had been sumessfully stripped out of the modified soybeans. The ne)d step, says Anthony Kinney from Pioneer, is to test for allergic reacfions in pigs and then humans. Before the soybeans could be sold as hypoallergenic, scientists will need to find a way of removing two other proteins that also trigger allergic reactions. Kinney says this should not be difficuft. While it is rare to find natural soybeans minus the P34 gene, some wild species already lack the pnes for the other allergenic proteins. Byjudidous breeding of these wild strains you might only need to knock out P34 to get hypoallergenic soybeans. But gene silencing might not solve the pmblem permanently. Because the P34 gene is still intact in the modified soybeans, a random mutation or vifral infection might conceivably turn it back on. But Kinney says this is highly unlikely.
"More than half of all allergic reactions to soybeans are caused by one protein. The allergy mostly shows up as hives, itchy skin and diarrhoea"
In practice the technique suppresses genes completely and permanently. Besides, he says, murine testing of the 6M beans would pick up any failure in the gene silencing technique. Kinney says they plan to produce soybeans wfth all the allergenic proteins knocked out. But demand is likely to be low, at least initially. A small market could exist fbr hypoallergenic soybean formula fbr infants, although aftematives like rice-based formula already exist. Adults who are allergic to the beans are more interested in avoiding soya that is used as a filler in precessed foods. But this soya could come from a variety of different sources. So unless all soya becomes hypoallergenic, a 6M version will not be of much benefit. Modified fbods that are safer to eat could address complaints that all of 6M's benefits now go to corporations and farmers, while consumers bear all the risk. But Jane Rissier, a staff scientist who specialises in biotechnology policy at the Union of Concerned Scientists in Washington DC, says if and when they appear, non-allergenic fbods will not end the debate. They will simply be one more factor to consider when deciding whether the benefits of biotechnology outweigh the risks. Kurt Kleiner.
End of female circumcision'? ROB EDWARDS, JOHANNESBURG
GENITAL mutilation and other barbaric traditions already inflicted on over loo million women have been rejected in a last-ditch deal sealed at the World Summit. Over igo countries have agreed that healthcare services must conform to "basic human rights and fundamental freedoms", a provision designed to prevent female circumcision. The custom is still common in many cultures, where it's considered an essential rite of passage to womanhood. The practice, where young girls have part or all of their clitorises cut out to reduce their sexual desire, can cause severe pain, ulcers, urinary problems and infections, as well as psychological scars. According to the World Health Organization, this prospect still faces 2 million girls a year in parts of Africa, Asia and the Middle East. The new agreement was reached at the eleventh hour in johannesburg last week, after fraught late-night negotiations. Women's rights campaigners say it will also discourage other traditions like "honour killings", in which women can be legally murdered for betraying their husbands. European and Canadian ministers were unhappy about the wording of a draft agreement which said only that health services should be delivered "consistent with national laws and cultural and religious values". Without a counterbalancing reference to human rights, they argued, this sanctioned genital mutilation. So the ministers pushed to insert a clause insisting that health services also conformed with human rights and fundamental freedoms. They were backed by women's groups around the globe, including the Women's Environment and Development Organization in New York. Negotiations over the amendment shed an interesting light on the murky world of intemational diplomacy. The US opposed the amendment along with the Vatican and Islamic nations, an unusual alliance of countries critics have dubbed the 11 axis of medieval". They say the US and the Vatican were concerned that mentioning human rights could be seen as an endorsement of abortion and contraception. According to British officials, the US was persuaded this would not be the case at a key meeting with the European Union and Canada. After opposition by the US to the human rights clause crumbled, other countries gave way and agreement followed. The US government, however, insisted that it had not objected to the clause itself, but to the principle of reopening a contentious issue at the last minute. If this had happened in other cases, a State Department source told New Scientist, "Johannesburg would have gone up in flames.' The US said it only accepted the amendment because the South African goverrunent, which chaired the summit, proposed a special procedure which enabled the reopening of previously agreed text for a single change. But British officials maintained that the underlying concem of the Americans was abortion. This interpretation is home out by the formal "explanation of position" which the US issued at the end of the Johannesburg Summit. It said that any references to health rights and freedoms in the final action plan could not "in any way be interpreted as including or promoting abortion". It's not the first time the US had formed unlikely strategic alliances, officials pointed out. At a United Nations special session on children in New York in May, the US sided with Iraq and Somalia in defence of the death penalty for children. On that occasion they succeeded in weakening the session's final declaration. *
Will one get away?
To prevent its genetically modified salmon devastating wild populations if they escaped, a US company plans to make them all sterile females. But the approach may not be foolproof
A FIERCE debate still rages about the effects of releasing various genetically modified organisms. But most scientists and campaigners agree on one thing: GM fish could create havoc if they escaped and interbred with their wild cousins, or outcompeted native species. So US company Aqua Bounty, which is eager to start selling millions of GM Atlantic salmon to fish farmers around the world, plans to make them all sterile females. The question facing regulators is, will that be enough?
The company's AquAdvantage Bred salmon have an extra gene for a growth hormone, making them grow up to six times as fast as normal, though adults are no larger. Other groups in the US, Australia, Cuba and China are also creating fast-growing super fish. There are also plans to make fish more disease- resistant, more nutritious and able to withstand icy waters without freezing. If the potential benefits - at least for producers - are great, so are the risks. Last week, Britain's Agriculture and Environment Biotechnology Commission (AEBC), which advises the government, called for a complete ban on GM fish farming in pens open to natural waterways until there are "watertight" technologies for preventing fish from escapingandbreeding. Such escapes are inevitable if Aqua Bounty's salmon are grown in nets floating in coastal waters, like most farmed salmon. Hundreds of thousands of these get away each year. Critics are also concerned about the leakiness of US regulations. The Food and Drug Administration is the main agency involved in approving AquAdvantage fish for sale, on the basis that food quality could be affected. But since the added gene comes from the Chinook salmon, few are worried about food safety. "The environmental concems here are greater than food safety concems," says Rebecca Goldburg, a senior scientist at the Environmental Defense Fund. "And I'm concerned the FDA doesn't have the framework in place to evaluate this on environmental grounds."
Advocates of the technology have long argued that the damage such fish could cause would be limited. Transgenic animals tend to be less hardy, they argue, so natural selection would weed out them and their descendants if they escaped. While some GM fish are less hardy, though, they can be better at reproducing. According to the "Trojan gene" theory of William Muir and Richard Howard at Purdue University in Indiana, a population of GM fish could drive a natural population a thousand times larger to extinction in just 40 generations (New Scientist, 4 December 1999, P 4). Even making fish sterile doesn't solve all the problems. Sterile males can still lure females into unproductive matings that could threaten endangered species. Aqua Bounty wants to use two types of biological controls to tackle these concems. First, all their fish will be produced by mating females with other females masculinised by exposure to hormones. These fish can produce sperm, but all their offspring are female. The freshly fertilised eggs will then be subjected tO 20 times atmospheric pressure, which stops them from ejecting an extra set of chromosomes. The resulting fish are "triploid": they have three sets of chromosomes instead of two. "That makes the fish sterile," says Aqua Bounty vice-president Joe McGonigle. Triploid female salmon have highly atrophied ovaries and, unlike triploid males, don't attempt to mate. The process of making only females is considered infallible. And McGonigle argues that the pressure technique for triploidisation has proved its worth in the lab. "In our experiments with Atlantic salmon the process is ioo per cent," he says. "But I'm not asking the FDA to take my word on this." McGonigle says his company will verify the technique in larger batches and regularly sample fish to assure their sterility. But Muir isn't convinced. "They haven't looked at numbers high enough to make the bold statement that their method is foolproof," he points out. "Every process is imperfect and occasionally fails. I don't see why this should be different." One way to guarantee that all the fish are sterile would be to check every single one. lt sounds impractical, but it is already done in Florida, where triploid grass carp, voracious vegetarians from Asia, are released to control exotic water weeds. A blood sample from each fish is tested. McGonigle agrees that this would be possible, but he questions the reasonableness of testing every single fish. "Every industry does quality control by sampling," he says. "If it is good enough for producing drugs for humans, why wouldn't it be good enough for producingflsh?" Adopting universal testing would make it difficult for Aqua Bounty to sell fertilised eggs, since these cannot be tested without destroying them. Yet in US states where universal testing of grass carp isn't enforced, experts believe a few fertile fish have slipped through and begun breeding. There are other worries, too. It is well known that some triploid oysters revert to their normal diploid state. And there have been reports of some "triploid" fish that are actually mosaics. While their blood may be triploid, their genitals may not be. Neither phenomenon has been reported in salmon, but the issues haven't been extensively studied. Then there's the possibility of human error, or just sheer stupidity. In Washington state and Oregon, for example, some breeding stations for grass carp were built in flood-prone regions, allowing fertile grass carp to escape during floods. With such lingering doubts about triploidisation, the issue for regulators is whether even a low risk is acceptable. "Once the [fish] has escaped, there's virtually nothing that can be done to recall it," points out Malcolm Grant, the chairman of the AEBC. Thomas Chen of the University of Connecticut in Storrs, who works on GM crayfish and other species, thinks such animals should not only be made sterile, but also kept in a closed system, with a gauntlet of barriers separating them from any natural waterways. "There just hasn't been enough study of what happens when any transgenic mixes with a natural system to rely on ohe technique," he says. In the past, such land-based systems have never been feasible for salmon farming. They cost about a third more to build and run. McGonigle thinks there is only an argument for them where native species could interbreed with GM salmon, such as in the US and Canada. "[But] that would make it hard to compete with cheaper ocean pens in Chile, Tasmania and Argentina," he says. "North America would be out of the business and we wouldn't want to do that.' Still, ocean pens are themselves controversial, because of the streams of waste they produce. Land-based systems using recirculated water would allow farms to optimise water conditions for growth, and reduce losses from predation and disease. By lowering costs, transgenic fish could help make such systems viable. "That transgenic fish could end up moving salmon farms out of coastal waters is quite intriguing," says Goldburg of the Environmental Defense Fund. "In that case, my opinion of the technology may begin to change.'
COMING SOON TO A TANK NEAR YOU
WHILE most companies producing GM fish want to put them on your dinner plate, others are keener to create a feast for the eyes. Aquariums could soon be home to a glowing green zebrafish created by Taiwanese company Taikong. The TK-1 contains the gene fbr a luminescent protein from jellyfish. Similar fish are the stock- in-trade of genetic researchers, but Talkong is the first to try and exploit what lt sees as a large market for mere profit.
Gene tweak will banish bad hair days
GET ready to bin those peroxide dyes and blue-rinse tints. Genetically modified hair in all shades and colours is coming to a salon near you, although you may he a bit grayer by the time it arrives. Researchers have turned the hair of lab mice a striking shade of fluorescent green. "They're punk mice, you could say," says creator Ronald Hoffman. It will be some years before GM hair makes it into the salons. But the pioneering experiments raise the prospect of restoring colour to graying hair, and could herald future treatments for baldness. Hoffman's team at biotech company AntiCancer in San Diego, California, created the mice by inserting a jellyfish gene into the animals' hair follicles. The gene makes a protein that glows green when bathed in blue light.
To insert the gene, the team first incorporated it into an adenovirus similar to the one that causes colds. They also plucked out genes that enable the virus to replicate, so that it would load its genetic cargo into mouse cells without infecting the re ' st of the animal. They then grew small sheets of mouse skin, softened them with an enzyme called collagenase, and dunked the skin into a solution containing the gene-laden virus. Within hours, Hoffman was able to peer down a microscope and see blobs of the fluorescent green protein appearing in hair follicles, the source of each new shaft of hair (see Graphic).
"The pioneering experiments raise the prospect of restore ng colourto graying hair, and could herald treatments for baldness"
In the slivers he had treated, 8o per cent of the growing hairs had turned green. When he grafted the slivers onto mice lacking hair of their own, the transplanted hair continued developing normally in every way (Proceedings of the NationalAcademy ofsciences, DOI: 10-1073/pnas.192453799) Hoffman warns that the breakthrough is very much a first step. Before we can treat baldness the same way, we will have to identify the genes that cause it. But it may one day be possible to insert genes into hair follicles which suppress the overproduction of the hormone dihydrotestosterone, which is suspected of causing male pattembaldness. Using the GM technology to alter our usual hair colour might be easier, however. Hair colour is govemed by the amount and form of the pigment melanin. People with black hair make a form of the pigment called eumelanin, while ginger and brown hair owe their hue to a lighter form, called pheomelanin. Hoffman suggests that a simple hair cream could be used to switch the genes that control these pigments on or off. But if your ambition is to become a natural blonde, prepare for a disappointment, as no one yet knows the molecular secret of blonde hair. "It's one thing to restore pigment formation to a graying follicle, but quite another to modify the pigment," says Hoffman. He now plans to experiment with albino mice, to see if it is possible to insert the missing tyrosinase gene which produces the melanin pigments.
How mothers-in- law got a bad name
IF RELATIONS with the in-laws are a little strained, spare a thought for German peasants in the 18th and 19th centuries. for them, having Dad's mother amund could double the chances of a child dying. From an evolutonary point crf view, it makes sense for a mother's parents to take more of an interest in a grandchild than the father's parents. While mum's mother can be sure she's cooing at her own flesh and blood, there is always the chance that dad - and his parents - have been duped into looking afterthe milkman's kid. Studies often flnd that paternal grandmothers have less of a positive influence on a child's health, butforthe flrst time, they have now been shown to have a negative effect. Eckart Voland at Glessen University in Germany and his colleague Jan Beise leafed through church registers from the Krummhdrn region of northern Germany for birth and death data on low-income families. They found that if a mother's mother was alive when the child was between 6 and 12 months old, it was 79 per cent more likely to survive than if she were dead. Voland thinks the positive effect is strong at this point in the child's development because the mother's mother helps her with weaning. But if the fathees mother was around, the child was half as likely to survive as they would have been if she were dead. Voland thinks that in the strict religious society then prevalent in the region, a man's mother might have been overly suspicious of a baby's paternity. The harassment of the mother may have had a negative effect on the child's care. So the "evil mother-in-law", while rooted in evolutionary conflict, is probably more a cultural phenomenon, he says. But Haraid Euler, an expert in the evolution of family relationships at Kassel University in Germany, thinks there may be more going on. "The son can also get grandchildren by having sexual relations with other women," he says. This would be in the grandmother's interests, provided the mother continues to care for the child. lt might pay the father's grandmother to destabilise the relationship, freeing her son to explore pastures new. James Randerson
RNA processing immunity
An ancient immune system hiding in our cells has the power to switch off genes at will. We could soon be harnessing this awesome force to stop cancerand viruses dead, says Philip Cohen
ONE night last July, biologist Anton McCaffrey was driving north towards San Francisco when a Califomia Highway Patrol officer waved him over. "Approximate speed, 87 miles per hour. Whoops," McCaffrey recalls. But the excuse he offered to the cop was certainly original: he was having troubld concentrating on his speed because his mouse livers had stopped glowing. just hours earlier in his lab at Stanford University, McCaffrey explained, he had seen the first results of an experiment that could revolutionise medicine. McCaffrey and his colleagues were trying to shut down the activity of a gene in living mice, using a completely new type of drug. They had engineered the mice to produce a glowing protein whenever and wherever the gene was active. This meant that normally, these mice would be scampering around with glowing livers. But after months of painstaking research they had at last succeeded in switching off the gene and getting rid of the glow. "The officer just gave me a blank look," he says. "But he did cut me a deal on the ticket."
It was a pretty impressive achievement, even if the cop didn't realise it. No one had ever succeeded in switching off a gene in living mammals in this way before. McCaffrey's team had snuffed the gene with the help of an ancient immune system that up to a few years ago was thought to be present only in humbler organisms such as flies, worms and plants. It's a discovery that has astonished and excited biologists. By showing the same system was lying unnoticed in mammals and could be harnessed, the work paves the way for a completely new technique for tackling human disease, by switching off genes at will. It's a tool that promises to help us attack rogue genes in cancer and beat back the viruses that cause AIDS and hepatitis. This newly discovered immune system is called RNA interference, or RNAI, and is one of the most exciting new areas in biology. "This used to be a small, exotic field," says Thomas Tuschl of the Max Planck Institute for Biophysical Chemistry in G6ttingen, Germany, whose lab first found RNAI lurking inside human cells little more than a year ago. "Now people are flooding in to explore the possibilities." Labs and companies are scrambling to exploit its potential. Such is the hype that one British broadsheet hailed it in a lead article as "a revolution" and "a genetic discovery to change the world". And with good reason. The RNA immune system promises to give us new weapons in the war against disease, and it has certainly overturned some cherished notions about biology. But although researchers are optimistic and the results of the experiments spectacular, no one can yet answer the key question. Will the RNA immune system live up to its promise in the clinic? Like many remarkable distoveries, scientists stumbled upon RNA interference entirely by accident. A decade ago, Richard Jorgensen, now at the University of Arizona, and Joseph Mol, working independently at the Free University in Amsterdam, were experimenting with genes for flower colour in petunias. Both of them gave the flowers an extra copy of a gene coding for a purple pigment, expecting to produce a more intense colour. But often the flowers were simply white, suggesting that the extra gene not only played dead but somehow stopped the plant's original pigment genes from working. This discovery left the teams scratching their heads. Adding more genes should only boost the levels of protein encoded by those genes - making the flowers deeper purple, not white. Meanwhile, flowers weren't the only organisms flaunting their disregard for genetic theory. other researchers working on the mould Neurospora crassa and the tiny soil nematode Caenorhabditis elegans were also finding that adding extra genetic DNA, or even just incomplete RNA copies could actually result in less gene activity. The researchers were stumped. Their findings completely contradicted every tenet of textbook biology. It's supposed to work like this. The genes in a cell's chromosomes are made of a double helix composed of two strands of DNA. Each strand has a backbone that sports a string of "letters" consisting of chemical bases named A, C, G, T. The bases on the two strands pair up, A with T and G wfth C, zipping the strands together. When a gene is switched on, the cell "prints out" a copy of the gene's letters on a single strand of RNA, a molecule rather like DNA except with T replaced by U. This printout, called messenger R,NA, then gets shuttled off to protein factories called ribosomes, which read off the sequence of letters. The RNA printout tells the ribosomes which amino acids to use to build the protein encoded by the original gene. Basically, genetic information is transcribed from DNA into RNA, which is then used to make proteins. So according to this orthodoxy, RNA's role is rather limited and lowly - the messenger boy of the cell. Biologists took all this pretty much for granted.
Blocking the flow But Jorgensen's peculiar petunias gave the first clues that there could be more to RNA than this simple role. Researchers realised that when they added a gene to a cell, any of the cell's own genes that had a similar sequence got shut down. It tumed out that the messenger RNA from these genes was being destroyed before it could be used to make a protein. The flow of information from DNA to protein was being blocked, but no one knew how, or why. A big breakthrough came four years ago from Andrew Fire at the Camegie Institute of Washington in Baltimore, and a team at the University of Massachusetts. They discovered that a potent trigger for this gene shutdown was double-stranded RNA - two strings joined together just as they are in the DNA double helix. Most cells have only single-stranded RNA, but some viruses have the double- stranded variety. Suddenly the cell's motivation was perfectly clear: it thought it was under attack and was trying to close down the supposed invader's genes. It seems that one function of this RNA defence is to attack suspicious gene sequences that might have come from viruses or other genetic parasites, rather like the way the body's main immune system attacks suspicious proteins - or policemen pull over cars going suspiciously fast. It's obvious why double- stranded RNA should set alarm bells ringing. It's less clear why some artificially inserted genes are also identified somehow as troublemakers. In petunias, one theory goes that adding the extra purple genes could, for reasons that are only poorly understood, result in the formation of strange RNA structures that trigger the defence mechanism. But however the cell sniffs out foreign DNA, once it does the cell starts shutting it down, along with any similar genes. Normally, this isn't too much of a problem because most virus genes have very different sequences to plant genes. The discovery of RNAI was a dream come true for many researchers. Here at last was a way of shutting genes down at will. But even though the technique works well in practice, researchers are still trying to understand how RNA interference works in different animals. So far, they've had most success in animals such as fruit flies, starting with double- stranded RNA as the trigger (see Diagram, P 33). Researchers now suspect that there is a similar mechanism in mammals, except that the trigger may be different. The pairing between the bases in DNA and RNA is key to how RNAI works. When double- stranded RNA enters the cell, its unusual structure rings alarm bells. An enzyme called DICER quickly slices it up into short double- stranded pieces, like a knife slicing up a baguette into chunks. The cell then peels the two strands apart and uses them as probes to seek out matching messenger RNA strands, which they stick to because their bases pair up exactly. Once these probes are stuck to the rogue messenger RNA, they destroy it with the help of other enzymes. This effectively shuts down the unwanted gene. "It's much like the strategy a human programmer uses to track down computer viruses," says Fire. "They use a piece of viral sequence long enough to be specific, but small enough not to encode a dangerous piece of the virus." At that point, geneticists had a field day using double-stranded RNA triggers to take out any genes they chose in animals such as flies and worms. But hopes of using it in human cells were scotched. That's because most mammalian cells have a completely different response to double-stranded RNA. They commit suicide in spectacular style, shutting down all protein production and putting their genetic material through the shredder. For good measure they spray out a chemical called interferon that warns surrounding cells of a potential viral invasion. It seemed to the researchers that this rather drastic defence mechanism had taken the place of the RNA immune system in our cells. But Tuschl's team realised there was another explanation, as did Fire, working independently in collaboration with Natasha Caplen at the National Institutes of Health near Washington DC. Perhaps the system was still alive in mammalian cells, they guessed, but had simply been masked by the suicide program, which was an extra level of defence. Other researchers had noticed that you had to add big pieces of double-stranded RNA - at least 30 letters long - to trigger the self- destruct program. So the two teams wondered what would happen if they bypassed the first step of the RNAI pathway and just added ready- chopped pieces of RNA, dubbed "small interfering RNAS", or siRNAs, instead.
Back from the dead
They struck gold. Both groups found that when they fed these RNA pieces to mammalian cells, they could shut down genes at will without causing the cells to commit suicide. In other words, the ancient RNA immune system was ready and waiting in our cells, and researchers had finally found a way to bring it to life. Mammalian geneticists were at last free to join the party, and many labs are now knocking out various genes with gusto in the hope of finding out what they do. Gregory Hannon and his team at Cold Spring Harbor Lab in New York, for example, are part of a multi-centre effort to knock out 15,ooo different genes in various human cancer cell lines. But it's the therapeutic potential of our newly discovered immune capability that is drawing the most excitement. It promises to open up a new avenue of attack against old viral enemies such as HIV and hepatitis. And in a flurry of publications this year, researchers proved that in animals at least, RNAI can produce spectacular results. This May, for example, John Rossi and his team at the City of Hope National Medical Center near Los Angeles used RNA interference to reduce the activity of HIV genes in human cells by a factor of lo,ooo. Soon afterwards, in July, Phillip Sharp and his colleagues at MIT in Boston announced that they could slow down virtually every stage of HIV's life cycle by pommelling cells with siRNAs. Next came the key "glowing livers" experiment, performed by McCaffrey with Mark Kay and his colleagues at Stanford and Gregory Hannon and his colleagues at Cold Spring Harbor in New York state. The gene they shut down belonged to the hepatitis C virus, and it was the first time anyone had got RNAI to work in live mammals. Anyone who feared it might be a fluke didn't have to wait long for supporting evidence. Within a few weeks, David Lewis and his colleagues at Wisconsin-based company Mirus published a similar experiment showing RNAI could suppress genes in mouse liver, kidney, spleen, lung and pancreas. In August, scientists at biotech company Intradigm in Rockville, Maryland, announced another success: they had used the method to slow the growth of mouse tumours. Not surprisingly, companies and labs are scrambling to get on board the RNAI bandwagon. "I've been to many meetings that aren't about RNAI, but it is quickly pencilled into the schedule at the last minute," says Lewis. Even at a time when funding bodies are still shell-shocked from the dotcom collapse, this bold new idea isn't going begging for cash. Sharp, Tuschl and David Bartel at the Massachusetts Institute of Technology and Phillip Zamore of the University of Massachusetts Medical School in Worcester are in the process of forming a company called Alnylam to develop RNAI therapeutics. Even at this early stage, they have managed to raise $15 million. Mirus has also attracted millions of dollars to pursue RNAI research. It's not just the initial results that have impressed potential investors. RNAI isn't the first RNA-based technology to have raised hopes for a radical new treatment - but it does have key advantages over previous strategies. Only a few years ago biologists were fired up about the potential of antisense RNA - single strands of RNA that block a gene's messenger RNA by binding to it, but don't trigger the RNA interference mechanism. Meanwhile other researchers were using "catalytic RNAS", which can chop up targets on their own.
Precision weapon But these two technologies have stumbled because they are hard to target accurately, and act by blocking the cell's biochemistry. In contrast, RNA interference is far more precise. What's more, labs report that RNAI is a more efficient way to destroy a target, which makes perfect sense to Zamore. "With other strategies, you are trying to block some cellular process," he says. "With RNAI you are just directing the cell's own biology. You and the cell are on the same side." That precision is good news for gene therapists. They can already add gene activity to cells, but would dearly love to be able to block genes as well. It could be invaluable in treating genetic diseases such as Huntington's, which is caused by a rogue protein that disrupts cell physiology. Researchers could use the RNA immune system to shut down the gene that codes for the rogue protein while using conventional gene therapy to add a healthy copy. Still, despite the recent flood of papers, researchers acknowledge that RNAI therapeutics are still an unproven idea. "These are proof-of-principle experiments," says Sharp. "Between this and the clinic is a long and tortuous path . Kay agrees. "We're p'fetty excited about it, but the question remains if there are going to be limitations as we go forward," he says. One obvious question mark is how easy it will be to deliver RNAi-stimulating drugs to a patient's cells - and how often it would need to be done. Both Kay's and Lewis's groups used high-pressure injection to deliver siRNAs to mouse tissues, but the effect dwindled after 3 days. Neither thinks this will work well in people because human bodies are too big. So the teams are working on other strategies. Kay's team is adapting the viruses used for gene therapy to furnish cells with genes that code for siRNAs. Mirus is using chemistry to make artificial viruses that they hope will be able to target siRNAs to particular tissues. Delivery isn't the only issue. Controlling the behaviour of the RNA immune response once it has been unleashed could prove tricky. In plants, the RNAI response can spread from cell to cell, travelling through 30 centimetres of plant tissue. In worms, RNAI reactions can spread even more impressively: the gene shutdown can be transferred from a mother to her offspring. Whether this strange form of heredity exists in other animals is unclear, but Craig Hunter and his team at Harvard University in Boston have found that a protein involved in these properties of RNAI is also found in mammals. If RNAI can spread through human tissue, this could make it an even more powerful therapeutic - or make it harder to control.
Another limitation is that RNAi may not work in all tissues. And the precision of the technology may occasionally work against it, Since viruses such as HIV can mutate so rapidly, they may soon alter their DNA to evade a wide array of siRNA drugs. indeed, some viruses in plants and flies have already evolved defences against RNAI, although such anti-RNAi tactics haven't yet been seen in human viruses.
What's more, it may well be important not to overwork the RNAI machinery, because it may have other jobs to do besides tackling viruses. Genomes are littered with potentially destructive pieces of DNA called transposons, which can jump from place to place, disrupting genes. In worms, for example, a failure of the RNAI machinery causes the transposons to activate, suggesting that RNAI helps suppress these renegade pieces of DNA. That raises the worry that enlisting RNAI to fight viruses for us could leave us vulnerable to our genomic parasites.
But despite these caveats, our new-found line of cellular defence is the most promising therapeutic avenue to have emerged for years. And the revolution that RNAI has triggered isn't confined to medicine: it has entirely altered the way we think about biology. When the RNA immune system isn't busy fighting off invaders and policing parasites, it has some important civilian duties. Far from being a mere messenger boy, RNA plays a key role in controlling normal genes in a cell - a complete reversal of the traditional view of its role. It may even be crucial to the development of all animals and plants.
One the best examples comes from a gene called let-7. It was first seen in C elegans, but researchers have now found it in many animals, including flies and humans. A mutation in the let-7 gene produces a defect in worm developmeiat. But the gene doesn't code for a protein. It makes a single-stranded 70-letter RNA molecule that then loops back on itself like a hairpin to form a double- stranded molecule.
Tuschl and Zamore showed recently that this hairpin is processed by DICER to produce 11 microRNAs". Rather like siRNAs, these microRNAs bind to messenger RNA, but they don't degrade it. Instead they simply stop the cell's protein factories from reading the message and making a protein. This proves that RNAI is more than a one-trick pony. it is a complex machine that can be programmed by different RNAs to perform different tasks. When let-7 was discovered, it was one of only a few strange genes coding for hairpin RNA. But in the past year, researchers have found that a wide variety of organisms, including humans, may have hundreds of genes for microRNAs, with different tissues producing different ones. It looks like RNA plays a key role in managing the biochemistry of the cell.
In a nice twist that truly tums the biological orthodoxy on its head, it transpires that RNA can even end up in charge of DNA. In plants, for instance, the RNA immune system can trigger the complete shutdown of genes so that they don't even get as far as making messenger RNA. And experiments with yeast suggest that DICER and other parts of the RNAI machinery help to shape centromeres, the structures within chromosomes that guide them to the right places when the cell divides. If that turns out to be true for most organisms, it would put RNAI slap bang at the heart of chromosomes and biology.
For all the excitement surrounding RNAi, the remarkable fact is that its discovery didn't depend on genomics, proteomics, bioinformatics or any other high-tech innovation of modern biology. in fact, many experts have noted that nearly all the biochemical and genetic techniques behind its discovery were available 25 years earlier. As to why it took scientists so long to find this basic player in biology, there are many views.
Some experts think the dogma of molecular biology blinded researchers to the role RNA might play in influencing the flow of information. And the fact that siRNAs are so tiny also helped them elude detection. "Any RNA that small, people just assumed was degraded and threw it away," says Sharp. However, he is convinced that the delay in recognising RNAI comes down to a simple fact: no one was looking for it very hard. "The mindset was and is that we already know everything about the biology of cells and are just filling in the details," he says. "This story should remind everyone there are still probably things out there we don't understand, or even know that they exist."
Boys or Girl?
LAST March Helen Lang had her fourth child, Catherine. it was a shock for her and her husband Chas and his family, who were convinced the new arrival would be another boy. Chas is one of three brothers, and between them they have produced six sons. Catherine is the first girl on Chas's side of the family for three generations. The family's propensity for boys could admittedly be down to chance alone - if enough people toss a coin enough times, someone's eventually going to get ten heads in a row. But could it also be something in the Lang genes? Something that Catherine's genes managed to overcome? Most of us think that the sex of our offspring is a matter of chance, a random process with an equal likelihood of producing a boy or a girl. But scientists believe that Mother Nature doesn't simply toss a coin. And it isn't just odd cases like that of Chas and his brothers that have convinced them. Records show that, worldwide, slightly more males are born than females - lo6 boys for every loo girls, in fact. Then there are all sorts of other strange findings. For example, high-status men such as presidents and lords tend to produce sons, but those who work as divers, test pilots, clergymen and sawmill workers have more daughters. More boys are born after unseasonably hot weather. older fathers and those under stress produce more daughters. And, during and after each world war there was a glut of baby boys. It looks as though under certain circumstances some men are more likely to have sons while others have more daughters. For several decades, researchers have been trying to work out exactly what's going on. But the picture is confused. Some studies are contradictory, and there's no coherent theory that encompasses all the research findings. But perhaps they've been looking for explanations in the wrong place. Maybe it's not fathers who control the sex of their children. Maybe it's mothers. That's what Valerie Grant from the University of Auckland thinks. She's found that she can predict whether a woman is more likely to have a boy or girl just by using a personality test. Dominant women have more testosterone, claims Grant, and that's why they produce more sons. She's putting female biology at the centre of the debate about whether the sex of our children is a matter of chance or not. And it looks as though she may be onto something. Recent research has strengthened the link between testosterone and sons. And another study published earlier this year suggests that biologically fit mothers have more than their fair share of sons. Could research into sex determination benefit from being a bit less ... well, sexist? The idea that humans might somehow control the sex of their offspring isn't as odd as it might first appear. Many animals do it, producing young of the sex that will do best under the prevailing conditions. And it's usually the mother that takes control. In reptiles, environmental factors are often key. Female alligators, for example, produce sons if they lay their eggs in a relatively warm place and daughters if the incubation site is cooler. Insects such as ants, bees and wasps have an even more foolproof method: eggs that mothers allow to be fertilised become daughters, the rest become sons. Humans may simply be doing what comes naturally to many other animals. But there's a problem. Our sex is determined by our genetic make-up: if your 23rd pair of chromosomes is xx, you are female; if it's XY, you're male. Human embryos inherit an X from their mother and either another X or a Y from their father. And, in theory at least, men produce equal numbers of sperm carrying X and Y chromosomes. So on the face of it, we have no scope to affect the sex of our offspring.
Yet it's clear that environmental factors can disrupt the balance. For example, some pollutants seem to selectively damage sperm carrying either the X or Y chromosome. Men exposed to high levels of radiation at the Sellafield nuclear power plant in Cumbria have been found to father 40 per cent more sons than daughters. And only this year, a study showed that parents who smoke more than 20 cigarettes a day produce boys 45 per cent of the time, compared with 55 per cent for those who don't smoke at all. Sometimes the environmental influence isn't so clear, as with the finding that southern Europeans have more boys than northemers do. Victor Grech from St Luke's Hospital in Malta, who made the discovery two years ago, suggested that warm weather boosts production of Y-carrying sperm. But in April he reported that in north America the trend was reversed, with more boys born in Canada, and fewer the further south you go. "[This] puts a spanner in the works," says Grech. "Temperature does not play a role." Still, some environments undoubtedly favour boys and others girls. But the question remains: can parents actively, albeit unconsciously, exert control over their offspring's sex? In theory, such an ability could evolve and spread through the human race if any genes that made sex manipulation possible gave the people who carried them an edge over those who didn't. So what could be the survival advantage? Robert Trivers from Rutgers University, New Jersey, and Dan Willard from Harvard University tried to explain the evolution of sex-ratio skewing in mammals three decades ago. Their hypothesis, which remains the most influential in the field, states that parents have offspring of the sex that is likely to produce the greatest number of grandchildren. In polygamous species, a male can in theory fati!ter children by more than his fair share of females, but only if he can out-compete rival suitors. So if you can sire strong, healthy, attractive children, better make them boys because they raise your chances of having many grandchildren. But if you can't, then you had better play it safe with daughters, who are likely to produce at least some grandchildren. Although human societies tend to be underpinned by monogamy, plenty of polygamy goes on too, so you'd think we would be subject to the Trivers-Willard effect. If true, there are three ways it might happen. First, high-quality males might produce more Y-carrying sperm, and weaker males more X sperm. Nobody knows how this might happen, but one study did find that men with only daughters had 70 per cent X sperm. That suggests that at least some of the single-sex dynasties like the Langs might be caused by some real biological effect, rather than just a statistical fluke. Another possibility is that embryos of one or the other sex are more likely to miscarry. There's evidence that this happens in some other mammals but nobody knows whether selective abortion happens naturally in humans. Medical technology has, however, made it an option in recent years (see "Sexploitation", below). A third way that the sex of offspring could be skewed is if X and Y sperm have different success rates at fertilising eggs. There are various ways this might happen, but one factor thought to be important is the timing of conception during the menstrual cycle due to varying hormone levels. Studies suggest that conceptions produce more boys if they occur outside the woman's peak fertility, which is before or after the mid-point of the cycle. This could explain the high proportion of sons bom after the world wars and early in marriages, because frequent sex means fertilisation is likely to occur earlier in the cycle. So far, so good. But some researchers think we're still not seeing the whole picture. John Lazarus from the University of Newcastle- upon-Tyne has recently reviewed the research in this field and has found that of the 50 or so studies in humans that consider status and sex of offspring, virtually all focus on the father. But, he says, when you look at possible mechanisms you see that mothers could play an equally important role. "It takes two to have sex," he points out. And if a baby's sex depends on what point during the menstrual cycle it was conceived "then that's a female effect". Anthropologist Boguslaw Pawlowski from the University of Wroclaw in Poland agrees. "I think the mother is more important," he says. Earlier this year, Pawlowski and colleague Elzbieta Cieplak published findings from a study that they believe show a direct link between a mother's biological "fitness" and the sex of her baby (Medical Hypotheses, vol 58, P 15). They took the birthweight of a mother's first baby as an indicator of her physical condition and then looked to see if those who had previously had a good-sized baby were more likely to give birth to a boy next time around. For the 227 local women in their study, this proved to be the case. On closer inspection, however, the results were only significant if the firstbom was a girl. Then the bias was impressive: 64 per cent of mothers whose first daughter was below average weight had a girl the next time around, while 67 per cent of those who had a heavier- than-average first daughter subsequently produced boys. One possible reason why the - effect was significant only after a firstborn - daughter is that male fetuses are notoriously sensitive to a wide range of malign forces during pregnancy. So the birthweight of boys is not as reliable an indicator of a mother's intrinsic physical condition as that of girls. Pawlowski believes his study shows the Trivers-Willard effect in action. He also suggests a possible mechanism, pointing out that at conception the ratio of males to females is 130:loo, but that this drops to io6:loo by the time of birth because boys are more likely to miscarry than girls. "I believe women in poorer biological condition are more prone to miscarry male fetuses," he says. While Pawlowski gives a leading role to mothers, Valerie Grant in Auckland goes further, claiming sex determination is a one- woman show. "People everywhere have it ingrained in them that the father's big contribution to the reproductive process is the sex of the offspring," she says. Four decades of research have convinced her otherwise. It sounds odd, but Grant says she can predict whether a woman is more likely to have a boy or girl depending on her personality. She asks prospective mothers to fill out a questionnaire that measures dominance.
The test, which is also available for a fee on the Internet (www.sexratio.com), consists of 64 adjectives such as proud, free, bored, awed and arrogant, which women tick if the word applies to them. Sprinkled among them are 13 words linked with high dominance and women are scored on how many of these they tick. The average score is about 3. The test is impressively accurate for women with relatively high or low figures, although it is less precise for the majority with intermediate scores. Grant's records show, for example, that pregnant women who score eight or above have an 8o per cent chance of having a boy. The key is testosterone, she says. And her latest study with colleague John France confirms her assumption that women who score highly on the dominance test also have the highest levels of the male hormone (Biological Psychology, vol 58, P 41). Grant admits that other scientists are sceptical of her work, despite the consistency of her published research over the years. "People are simply not persuaded by psychological tests," she says. "The whole idea will only be taken seriously when I can demonstrate the reproductive basis." So she's working on a theory. "My working hypothesis is that the female produces an ovum each cycle, already adapted to receive a spermatozoon bearing an X or a Y chromosome," she says. Grant admits she doesn't know the mechanism, but points to studies suggesting that testosterone in the ovaries regulates egg development. She speculates that high testosterone levels somehow prime developing eggs to be receptive to fertilisation by Y sperm, and low testosterone primes them for X sperm. When it comes to the reason women manipulate the sex of their offspring in this way, Grant does not entirely subscribe to the Trivers-Willard effect. She claims it allows mothers to have babies of the sex they are best suited to nurture. We know that women react differently to boys and girls, says Grant, and babies of different sexes respond best to different sorts of stimulus. So there would be an adaptive advantage if a mother could have a child of the sex that suits her temperament. And that child might in tum also be a more successful parent. Grant's theories have been endorsed to some extent by work by John Manning at Liverpool University, who reported in July that both women and men have more sons if they have a long ring finger compared with their index finger Vournal of Theoretical Biology, VOI 217, in press). What could possibly be the connection with finger length?. Manning has previously shown that this physical trait is linked to high testosterone levels in the womb. "Grant may be right that emotionally independent and dominant women tend to have more boys," says Manning. But he's not convinced that this means mothers are in control of the sex of their children. of course, there's no reason why both males and females might not "try" to manipulate the likely sex of their children, but each using different mechanisms. Such competing, selfish genes might result in an evolutionary "arms race" which continues until the benefits of influencing an offspring's sex are outweighed by the harm caused by interfering with crucial reproductive mechanisms. But Grant, at least, is convinced that women have the starring role. She points out that, compared with males, females have such a huge commitment to the conception, nurturing and raising of offspring that they'd be expected to evolve the ability to produce babies of the sex that suits them. She says: "I think the evidence that the male has anything to do with it is very flimsy." 0 Further read ing: Sex Ratios, ed ited by Ian Hardy, Cambridge University Press (2002)
I think, but who am l?
Science - especially cognitive science - is challenging philosophy as never before. If philosophers are reluctant to look at things anew, it is because the latest research is shaking the foundations of their search for the truth, argues John Gray
WE BELIEVE we are radically different from other animals. We have ethical ideals. We engage in philosophical inquiry. We have developed a rapidly expanding body of scientific knowledge. No other animal displays these capacities. Yet the implication of recent scientific research is that the differences between ourselves and other animals are much more subtle and complex than we think. VVhat we take to be our most valuable achievements may actually depend on illusions - false or distorted views of the world and ourselves that are built into our natural ways of thinking and perceiving. We believe we are conscious agents capable of directing our lives. Science shows this to be a radically oversimplified view. So, too, does the best philosophy. David Hume, looking within himself, declared he found no enduring identity, only "a bundle of sensations". Hume was aware that most people believe they have solid and enduring identities. Equally, he knew that most philosophers endorsed this common belief. Yet he asserted that human beings are "nothing but a collection of perceptions which succeed each other with inconceivable rapidity and are in perpetual flux and movement". Hume's analysis implies that our sense of ourselves as continuous, coherent individuals is an illusion. Worse, Hume believed, this is a natural illusion. We have an inbuilt tendency to see ourselves as other than we actually are. For the majority of philosophers, this is heresy. Ever since Socrates, philosophers have aspired to a life based solely on true beliefs. Yet recent research suggests we are programmed to live on illusions. The late Francisco Varela, one of the founders of cognitive science, has given Hume's sceptical view of the self a rigorous theoretical underpinning. For Varela, the continuities in our behaviour are not the expression of a "self". They are more like the pattems of activity that can be observed in insect colonies, where the separate components of the colony coordinate their activities without the help of any conscious agent. Varela cites an experiment in which the most efficient nurses in an insect colony were removed to form a sub-colony. The results were illuminating. outside the main colony, the insect nurses foraged more and nursed less. Within the main colony, formerly low-level nurses increased their nursing activities. When the efficient nurses were retumed to the main colony, they resumed their previous activities. The upshot of this experiment is that, even though insect colonies do not have a conscious self, they have memory and can renew themselves. Varela suggested that each of us is like an insect colony. Our lives hang together, but not because we are directing and controlling them. The self - the stable, continuous subject we believe ourselves to be - is a mirage. Varela's scientific studies corroborate the intuitions, of a supremely accomplished philosopher, but most philosophers appear to be unaware of the findings of cognitive science. This indifference to neuroscientific research is nothing new. Ever since the early days of neuroscience, it has been clear that perception is an extremely complex activity, yet philosophers have continued to think of it as a passive process. Worse, they seem to think that our ordinary experience can be taken simply as given. I have always been puzzled by this, for it implies that philosophy cannot really change the way we look at things. It is true that university philosophy courses often begin by rehearsing a number of ancient sceptical questions. How do we know this is a table? Can we be sure that the sun will rise tomorrow? Questions like this are the stock-in-trade of philosophy teachers. But if philosophers query common beliefs, it is normally only to reinstate them later. When Wittgenstein - perhaps the greatest 2oth-century philosopher - declared that philosophy leaves everything as ft is, he spoke for most philosophers today. The possibility that our everyday beliefs and perceptions maybe delusions is not seriously contemplated. But our perceptions may be delusions for good reasons, and science may eventually explain why. Our experience tells us that the Earth is flat. Science tells us that it is (roughly) spherical. Relying on our senses, we believe that the Earth does not move. Relying on science, we know that it rotates on its axis and revolves around the Sun. Astronomy shows that our everyday perceptions are in some respects mistaken. It might be objected that these are examples -pf simple perceptual illusion: they do not show that our basic beliefs are at fault.
The trouble with this response is that it fails to grasp just how radically science challenges the common-sense view of things. The passage of time, for example, is an integral part of our everyday experience, but some physicists believe time may not be part of the scheme of things. it is common sense to believe that we cannot change the world just by observing it. Yet, according to some interpretations of quantum mechanics, that is precisely what happens. Whereas science expands our horizons beyond the confines of our ordinary understanding, philosophy ends by shutting us inside it. As someone working in ethical and political philosophy, I have been particularly struck by the way many philosophers uncritically accept ordinary ways of thinking about humans. Consider personal autonomy, which practically every contemporary philosopher believes to be a worthy ideal. When our actions involve weighty ethical issues, they should ideally be the result of conscious deliberation. This view presupposes that autonomy is a realistic possibility - but that is an assumption and cannot be taken for granted. The ideal of autonomy comes from Immanuel Kant, who took it from Christianity. The notion that we are the authors of our own actions makes sense in the context of the religious belief that we are made in the image of God. It makes no sense in terms of the view of humans that is emerging from scientific inquiry. For our lives to be dictated by our choices, we must - at least potentially - be conscious of what we are doing. Unfortunately for those who subscribe to this familiar liberal ideal, science suggests that our lives can never be wholly, or even mainly, the products of conscious choices. True, we can scrutinise our behaviour, and alter our habits. We can leam to act more skilfully. By developing these capacities we are better able to cope with our lives: through consciously reflecting on our behaviour we can identify habitual perceptions and responses that are ineffective or redundant, and take steps to alter them. These are surely conscious interventions in our lives. But they do not enable us to act more consciously. Rather, having acquired better habits and skills, we simply act more effectively. We are not making ourselves more like the conscious individuals we imagine ourselves to be. Many scientists have taken from philosophers the belief that consciousness - the stream of subjective experience - is a mysterious process that needs an explanation. But as Susan Blackmore and others have argued (New ScientiSt, 22 June, p 26), this may be a mistake. Much as we think of it as the most indubitable feature of our experience, consciousness may be an illusion. The idea of a stream of consciousness suggests a continuous flow of subjective awareness in which items intermittently appear. But in Blackmore's view, there is no stream. Rather, our perceptions are moment-to- moment constructions that emerge from our bodily interactions with the world. A tennis player does not consciously see the ball, and then retum the serve. She simply returns it. If we think of ourselves in this way, there is no need to posit the mysterious process that we traditionally call consciousness. Cognitive scientists such as Varela present a parallel view. They argue that we overrate the importance of consciousness in our lives. Freud suggested that much of our mental life is unconscious. More radically, Varela argues that many of our mental processes and activities can never be conscious. It is not simply that the tennis player needn't be conscious of what she is doing. If she were conscious, she wouldn't be able to do it. If she had time to consciously note her perceptions, the moment for action would have gone. Training can enhance her skill in returning a serve, and a part of that training will involve conscious learning. But the resulting skill is displayed in action that is too quick to be the result of conscious reflection or decision. For Varela, this illustrates a wider truth. Our minds are not continuous, unified entities, but collections of activities and perceptions that -as Hume observed - are in perpetual flux and movement. Many of these activities and perceptions are unconscious, and many can never be conscious. As far as our subjective experience is concerned, the sensation of selfhood is overwhelming. But scientific research confirms Hume's more careful introspection in showing that this sensation is a delusion. If cognitive science is right, the picture of humans that philosophers conjure up when defending ideals of personal autonomy is at least partly a chimera. other research supports this conclusion. Work by Benjamin Libet at the University of Califomia showed that the electrical impulse in the brain that initiates action occurs up to half a second before we take the decision to act. Our actions are initiated unconsciously. True, Libet allowed that we can veto what the brain has initiated, but it is unclear how we can ever know that we have deliberately exercised this capacity. For all practical purposes, it might as well not exist. Research by Michael Gazzaniga and colleagues at Dartmouth College in Hanover, New Hampshire, on people with split brains suggests that we have developed a capacity for delusion for a reason. One side of our brains seems to have evolved to create narratives about the world and our activities in it. Working with a war veteran who had had the connection between the hemispheres of his brain severed in an attempt to treat his epileptic fits, Gazzaniga discovered that the right hemisphere handles sensory inputs in basic ways, while the left hemisphere houses the ability to interpret our own thoughts, emotions and behaviour and develop accounts of how the world works. Our brain has evolved in this way, he concludes, in order to enhance our reproductive success. The upshot of recent scientific research is that our common-sense understanding of ourselves must be revised, perhaps quite radically. Yet, with some exceptions, philosophy goes on as if nothing much has happened. Hume's insights into the complex, discontinuous processes that are concealed by our ordinary sense of personal identity have not been followed up. (One of the exceptions is Derek Parfit's book Reasons and Persons, which attempts to work out what a Humean view of personal identity means for ethics.) Why is this? I believe the answer lies in what scientific knowledge means for our understanding of the human mind - including the philosopher's mind. From Plato through to Descartes and John Stuart Mill, philosophers have thought of our minds as instruments for seeking out the truth. Certainly, we often have false beliefs. But according to this tradition, there is nothing in the way our minds work that prevents us from achieving a true view of things. Yet if Varela, Libet, Gazzaniga and others are right, this traditional assumption must be revised. Science shows that we are not the unitary, conscious agents we think we are. We are assemblages of perceptions and behaviours, in which consciousness figures only intermittently. Intellectually, we can know that this is the truth about ourselves. Even so, in our everyday experience we cannot escape the sensation of selfhood. It is often suggested that our sense of selfhood is a product of cultural conditioning, but I think this is a way of dodging the issue. As far as we can tell, humans have always experienced themselves in this way. The protagonists of the Iliad and the Bhagavadgita are no different from us in the way they deliberate about their lives and decide what to do. The idea that the sensation of selfhood is a cultural construction is attractive because it suggests we can rid ourselves of the illusion simply by altering our cultural values. The findings of cognitive science show that this is itself an illusion. In moments of introspection or meditation, we may be able to glimpse just how insubstantial we really are, but in everyday life we cannot help feeling that we are solid, enduring subjects. We are hard-wired for the illusion of self. The idea that our minds are programmed to generate illusions goes against the grain of philosophers, but it is all of a piece with an evolutionary understanding of the human animal. Darwinism teaches that our minds serve evolutionary fitness, not truth. We are not pure, inquiring minds accidentally stranded in the bodies of animals. We are animals. Minds are as much products of natural selection as are digestive systems. Our view of things is a product of our practical activities - seeking food and mates, using and devising tools, competing and cooperating with one another. There is no reason to think that it mirrors the world truthfully. Equally, there are no grounds for thinking that we are what we perceive ourselves to be. Western philosophy insists on the differences between human minds and the minds of other animals. No one denies that there are important differences. After all, no other animal has developed science. But scientific inquiry suggests that the differences between us and other animals are not anything like as great as the Western tradition suggests. We may have a capacity for intellectual inquiry that other animals do not possess, but equally we have an inbuilt tendency to self-delusion that they lack. The picture of the human animal that is emerging from science will unsettle people who hold to traditional ideas about consciousness, personal autonomy and the like. The idea that the ordinary sensation of selfhood is an error we cannot shake off suggests that some of the most valuable and distinctively human aspects of our lives may rest on illusions. Along with most philosophers, many scientists have subscribed to an ideal in which we can ultimately come to live without illusions. Ironically, scientific research demonstrates that these illusions are essential features of our normal functioning. The best philosophy is like the best science. It changes the way we think about the world, and about ourselves. The world uncovered by science is in many ways quite different from that disclosed in ordinary experience. The challenge for science is to explain how the two are related. The challenge for philosophy is to show how we can live well in the light of this new, and in some ways deeply paradoxical, view of the human animal.