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Patently ridiculous NS 9 Dec 2000

The biotech gold rush is making a mockery of the world patent system

THE stampede to file patents on biotech inventions is bringing the patent system to its knees and may even create a new digital divide between rich and poor countries. Governments around the world are still debating whether to grant patents on inventions such as animals genetically modified to produce drugs in their milk or ttie sequence of a human gene linked to disease. But inventors themselves are filing so many patents, and the applications are so long, that patent examiners are buckling under the strain. Patent offices are legally obliged to publish applications and libraries must display them. Most patents only run to a few dozen pages, but in the past year the World Intellectual Property Organization in Geneva has handled 30 applications for biotech patents that were each more than 1000 pages long. Now the WIPO has had advance warning of two huge biotech applications, each over 140,000 pages. The European Patent Office (EPO) in Munich is sitting on a mountain of 7600 applications for biotechnology patents, many hanging in "limbo" at the request of inventors waiting to see if their drugs will be approved. This logjam is not helped by uncertainty over the European Union's 1998 Biotechnology Directive, which tried to lay down rules on what could and could not be patented. Only four countries had incorporated the directive in their domestic legislation by the deadline of July this year. And the Netherlands has challenged its validity in the European Court of justice. If the court rules in favour of the Dutch next year, the directive will be nullified. Ron Merchant of the British Patent Office is concerned about the burgeoning size of patents. "What brought it home to me was seeing an application arrive. There were six big cardboard boxes, like bulk boxes of printer paper. It blew my mind. Can you imagine an examiner having to read that much paper?" Patent offices are now trying to limit the size of applications and encourage inventors to file electronically. The WIPO now demands a surcharge of 150,000 Swiss francs f(>r paper applications more than 10,000 pages long. The British Patent Office is seeking legal advice on whether it can publish patents in non-paper form. The EPO and the Patent Cooperation Treaty offices will already accept either paper or floppy

discs, and are moving to online filing. The US intends to abolish paper by 2005, and 90 per cent of Japanese filings are already electronic because paper apphcations are surcharged. 'Paper publication will have to stop sometime, and that day is not far off," says David Newton, head of the British Library's science section. But there's a snag. This trend could undermine the principle that ideas in patents should be freely available to all. When a patent is published on paper, patent libraries around the world make it available for anyone to read. Access to electronic files requires computers with CD-ROM drives or an expensive phone connection. Researchers who lack such resources must compete for time on library terminals-if their library has any. "The poorest countries are already greatly disadvantaged when it comes to developing, filing and defending patents," says James Deane of the Panos Institute, a development think-tank in London. "This trend could throw up yet another obstacle to creating their own intellectual property, leaving them further and perhaps permanently behind the rest of the world." Barry Fox and Andy Cogbian

Doomed asteroids point to Earth-like planets fit for life NS 9 Dec 2000

PLANETS like our own could be common, say astronomers in the US and Canada. No one has spotted Earth-like planets outside the Solar System. However, the researchers have found a surprisingly large amount of the rocky material such planets would be made of around stars like our Sun. "We think this is a very exciting discovery," says team member Brian Chaboyer of Dartmouth College in New Hampshire. T'he usual techniques for tracking down "extrasolar" planets rely on detecting tiny changes in a star's motion caused by the gravitational tug of an orbiting planet. However, since stars are big and difficult to budge, this technique only works if the planet is a giant like Jupiter. a The team, led by Norman Murray of the University of Toronto, rea$oned that if rocky asteroids-the building blocks of Earth-like planets-were orbiting a Sunlike star, some would inevitably rain down on the star itself. Many of the asteroids that orbit between Mars and Jupiter have suffered such a fate. Chaboyer and his colleagues examined the spectra of 642 nearby Sun-like stars for signs of iron, a common constituenti-of rocky planets. They believed any iron sucked up by a star would get stuck in the star's outer "mixing" layer. "Since this layer generally accounts for only a few per cent of the star's mass, even a small amount of iron'pollution'should show up i in the spectrum," says Chaboyer. But the team had to find a way of distinguishing between iron from asteroids and any iron the star was born with. In a

paper submitted to Astrophysical Journal, they say that because Sun-like stars of low mass have thicker mixing layers than those of high mass, any collected iron will be more diluted in low mass stars and the spectral signature due to iron will be weaker. If the star's mixing layer were thin, then the signature of iron would be stronger. "This is exactly the pattern we found," says Chaboyer. "It was a striking result." If all the iron in a star was homegrown, the thickness of the mixing layer would not affect its iron signature. Other astronomers urge some caution. 'However, ff the correlation holds up under scrutiny, then it is clearly a reasonable hypothesis that the increased iron comes from rocky material from which the primordial hydrogen and helium has been stripped," says Simon Jeffery of Armagh Observatory, Northem Ireland. As a further test of the idea, the astronomers looked at older Sun-like stars which hid exhausted the hydrogen fuel in their cores. These are known to have very deep mixing layers. "Sure enough, their iron was very diluted relative to the other stars just as would be predicted if the stars were accreting material," says Chaboyer. The surprising thing was that 80 to 90 per cent of the stars the team examined appear to be acgreting rocky material. 'It seems that the majority of stars like the Sun have terrestrial material around them," says Chaboyer. "This can only boost the chance of finding Earth-hke planets." Marcus Chown

More at: (Astrophysics e-print 001 1530)

It's a bug's lffe NS 9 Dec 2000

THE first bacteria on Earth had a much easier time of it than previously thought, despite living through massive asteroid bombardments. Between 4.15 and 3.8 billion years ago, storms of asteroids battered the Moon and Earth. While this "late heavy bombardment" was going on, the Earth's surface was uninhabitable, or so researchers used to think. That assumption was challenged a few years ago when Steve Mojzsis of the University of California at Los Angeles discovered hints of ancient life-in the form of telltale ratios of carbon isotopesin rocks that appeared to be more than 3.85 billion years old. Now Ariel Anbar and Gail Arnold of the University of Rochester in New York State have found that these rocks, from Akilia Island off Greenland, contain surprisingly small amounts of the metal iridium. When asteroids strike they deposit iridium, so Anbar reckons that while these rocks were forming, astemids were not raining down as heavily, making the surface more hospitable to life. "During most of this late heavy bombardment the Earth was a perfectly reasonable place for microbes to live," Anbar says. The worst impacts were 10 to 100 million years apart, and a handful of hardy bacteria could have survived at the bottom of the oceans to repopulate the planet. It would have been "a very bad time to try to develop any sort of advanced life", agrees Kevin Zahnle of the NASA Ames Research Center in California. "But not a bad time for bacteria." The work will be published in a forthcoming issue of the Journal of Geophyskal Research-Planets. Jeff Hecht

A wild gene chase NS 9 Dec 2000

FOCUS The biggest ever study of genes and disease is being launched soon, but will the doctors involved be able to cope?

OUR genes hold the keys to curing or even preventing cancers, heart disease, strokes and countless other serious illnesses. But the first step is linking genes to the right diseases. To speed the process, British researchers hope next year to start analysing DNA from half a million people in the Population Biomedical Collection. Armed with such information, doctors will eventually be able to spot people at risk from certain cancers and intervene early. Others at risk from heart disease, say, will be able to make pre-emptive adjustments to their lifestyle and begin treatment before their arteries start to clog. The Medical Research Council alone has pledged E20 million for the giant project. The Wellcome Trust says it will stump up further millions. These huge sums will be money well spent, say the leading lights of British medical research. The project is twice the size of the world's largest existing effort to chart the genetic roots of ilhiess in 270,000 Icelanders. So far, criticisms of these mega gene projects have focused on ethical concerns. Some observers have asked whether participants' gene secrets will be kept truly confidential (New Scientist, 2 December, p 7).

Too lime time

However, as the finishing touches are made to the British plans, a more pressing logistical concern is emerging: some experts fear Britain's hard-pressed family doctors will not be able to diagnose illness, record symptoms, and take medical and family histories with anything like the degree of accuracy needed. They wam that failure to make the right links between patients' symptoms and their genesphenotype and genotype-could even send researchers on wild goose chases after worthless drugs. One critic is Ronald Worton, president of the American Society of Human Genetics. "Getting the diagnosis right is crucial," he says. "If you don't, the genetics gives you the wrong answers.' ' ' But it's not only onlookers who have concerns. Even Mike Dexter, head of the mighty Wellcome Trust, which will pour some of its millions into the research, expressed fears at a genetics meeting at the Royal Society in London in September that general practice might not be equipped for the task. In theory, family doctors wil . I take personal and family medical histories of the 500,000 DNA donors. They will then report fresh signs and symptoms of disease to teams of geneticists. Armed with each donor's DNA, or "genotype", the geneticists would then look for common gene patterns in volunteers who develop specific diseases. But incorrect information, apart from misleading medical researchers, could make some people mistakenly think they are at risk of developing a serious disease. Conversely, doctors might miss people who are genuinely at risk. No one is blaming the family doctors themselves. In an ideal world, say critics, all the diagnoses and assessments would be done by trained clinical geneticists who know exactly the signs and symptoms of the diseases in which they are interested. This already happens in many studies linking genes, environment and disease. One example is the Avon Longitudinal Study of Parents and Children (ALSPAC) in Bristol that has been running since 1991. ALSPAC's clinical geneticists give the 14,000 children a painstaking annual examination lasting a whole afternoon, and have a meticulously drawn-up list of tests and measurements for each condition they are interested in. People recruited for gene studies by Gemini Genomics, a company in Cambridge, undergo 8-hour overhauls during which the investigators make between 500 and 1500 clinical measurements. Such thoroughness will be beyond the resources of the MRC/Wellcome study. The only affordable alternative, it seems, is to rely on family doctors. The trade-off is the added statistical power of the study gained by including so many subjects. So where are mistakes likely to appear? Ian Purves, head of the Sowerby Unit for Primary Care Informatics at the University of Newcastle, says that the most reliable data come from "hard" phenotypes such as cancer where you can get physical evidence of disease from biopsies of tissue. Something like asthma is more difficult to diagnose because symptoms and their severity vary greatly. "You can never be certain [of the diagnosisl," says Purves. Behavioural and psychiatric disorders are the ' most notoriously "soft" phenotypes, and pose diagnostic problems even for psychiatrists. David Weatherall, an eminent geneticist at the University of Oxford, has similar misgivings. He notes that, worryingly, even genetically simple diseases, where the illness is linked to a single faulty gene, can manifest themselves in a variety of ways. His own research on the blood disease thalassaemia, for example, has shown that patients who have exactly the same defect in the gene may be extremely sick, mildly ill or completely healthy. "This is the message, that even in simple monogenic diseases, the relationship between genotype and phenotype is complex," he says. Weatherall argues that the capacity for misjudging signs and symptoms will be massively amplified when the study looks at common multifactorial diseases such as cancer, heart disease and schizophrenia. Critics agree it would be unfair to pin the blame for such failings on family doctors. Most surgeries in Britain are stretched to the limit, with little chance of consultations longer than 10 minutes per patient. "In culling information about genetic risks, GPs face some significant problems," says Mike Pringle, chairman of the Royal College of General Practitioners. First, he says, it's difficult for GPs to establish family histories of disease. Second, patients themselves don't always know what their relatives died of. Third, there's a high chance in some parts of the country that the man a patient calls "father" is not the biological father. "You must accept there's no such thing as a complete and accurate medical record," says Pringle.

So is there a solution, or will the survey simply have to live with the expected errors? "If you think the phenotype is not clear enough, you must do a more specific project," says Purves. "You'd take a more detailed sample, and look at patients in more depth, but it's not affordable to do that across the board." But gome observers, such as Andrew Wilkie, a clinical geneticist at the University of Oxford, wonder why, at this stage of the project, precise guidelines have not been drawn up for all the GPs involved. He thinks each GP could be trained and equipped to take specific measurements which would at least provide unequivocal baseline data. 'There should be some kind of uniform protocol," he says. Tom Meade, who chairs the MRC expert working group that is refining the study, is confident of finding a solution. "We accept the importance of phenotype determination," he says. "But it can be tackled." One idea gaining favour is for highly trained reviewers at centres in each geographical region to go through each GP's data thoroughly, rating its accuracy and validity against a checklist of clinical signs. Any dubious reports would be discarded or investigated further. Another is for highly trained research nurses in surgeries to take detailed baseline data for each patient at the beginning of the study. "It's pretty labour intensive, and you need these reviewers, but reliable phenotypic data can be obtained provided you're willing to spend time and effort on it," says Meade. "Of course it costs money, and that will influence what we can do," he adds. "But I don't accept that we'll get results which are any less accurate than any other large prospective study." The value of the whole enterprise could in the end hinge not on the DNA itself, but on the accuracy with which each illness is dissected. Paul Kelly, the chief executive of Gemini Genomics, ptits it more bluntly. "Garbage in, garbage out," he says. Andy Coghlan

Move over Cassanova New Scientist 9 Dec 2000 When you're single no one wants to know. Yet the minute you get a partner the others come running. Ever wondered why? Jonathan Knight

BEFORE I got married a few weeks ago, friends told me that flashing a wedding ring was a sure way to attract female attention. Some said it was because women consider married men to be safe. Others said a wedding band is a quick way for women to identify a quality mate, one that's been pre-filtered by someone else. So in the interests of science, I have been spending more time in bars lately. As I sip my pint , I keep my left hand dearly visible and wait. And wait. So far, I would call the results inconclusive. It's really not afl that far-fetdied an idea, though. Females of other species copy the preferences of their peers all the time. Female quail, for example, prefer a male they have just seen copulating. And female guppies go for the more popular male, even if he is a bit of a wimp. Now researchers at the University of Louisville, Kentucky, have compelling evidence that people-particularly [email protected] in mate copying too. just hearing that other women want to date a man piques their interest. T'he effects of peer attention could factor into a variety of social phenomena: why a bushy beard and tangled locks were sexy in the seventies but today's hair can't be short enough, or why teens pierce parts of their bodies adults rarely even think about. They could help explain the unexpected sex appeal of Mick Jagger or jack Nicholson, and may be at work in celebrity of all @ds. Everyone wants to be unique, but when it comes to mating, imitation appears to have some powerful evolutionary advantages. Until recently, all the evidence of mate copying has come from fish and birds.

That's partly because it's easier to spot in these animals than in humans. Male grouse, for example, gather at special sites called leks where all the action takes place. Leks are the grouse equivalent of a singles bar. Here they strut around displaying their feathers in the hope of pulling a bird. Females wander through the lek, choose a male, mate on the spot-here the singles bar analogy breaks down a [email protected] then head off into the undergrowth to nest. Some males on the lek have all the luck. T'he most successful may win up to 80 per cent of the passing females. So what do the females see in these Casanovas? Some researchers suspected that mate copying was initiating a snowball effect: once a few females chose the same guy, the rest would come naming. In 1994, behavioural biologists tested this idea by placing several stuffed female dummies on a black grouse lek near randomly chosen mates. The eager cocks courted and mounted the dummies, sometimes for up to half an hour, which gave passing females lots of time to notice. Sure enough, the lucky males ended up mating with more real females on that day than either the day before or the day after. Other experiments in the lab showed a similar effect in fish known as river bullheads. Unlike male grouse, who play no part in raising their offspring, bullhead males are attentive fathers. They guard the eggs and stay with hatchlings until they are old enough to survive on their own. And female bullheads will always try to spawn with males that already have nests containing eggs. It looked as though both grouse and fish females were copying others as a shortcut to finding a good mate. True, there are other e)tplanations for these behaviours. In the case of the grouse, the females might simply have been stimulated by the sight of the males'prolonged encounters with the dummies-normal grouse copulations are almost instantaneous. Similarly, bullhead females might have other reasons for their preference. For example, by laying their eggs in nests that are already occupied, they decrease the chances of them being eaten by predators. But such objections to mate copying have been sidelined in recent years, in part because of the work at Louisville by biologist Lee Dugatkin. In 1996, Dugatkin got female guppies to diange their mind about which male they liked best solely on account of the preferences of other females. Normally, female guppies like orange. Given a choice, a female will go with the brightest orange male she can find. This may be because the most vividly coloured males tend to be the boldest, and will confront approaching predators. (The researchers added weight to this idea with an experiment in which they trapped a drab male in a glass cylinder and held him right up close to a large fish. Females that saw this happening subsequently preferred this drab male to a more orange one held further away) Dugatkin and his colleagues wanted to see if they could override the fish's genetically based preference for orange. They built a fish tank with two smaller tanks attached, one containing an orange male and the other holding a drab one. A female plopped in the middle tank would court the orange male through the glass. The same female was liable to change her mind, however, if she was first held in the middle by a clear cylinder while a second female was trapped by a Plexiglas divider so that she could only swim close to the drab male. For want of [email protected] better, she courted the drab male. When she was removed, along with the dividers, the original female would start courting the drab male rather than the orange one. Several other cases of mate copying have been reported since then. Last year David White and Bennett Galef of McMaster University in Ontario reported findings from a [email protected] experiment with Japanese quail using cages instead of tanks. In this case, the males were equally 'attractive" but one was allowed to mate with a female for ten minutes, while the other was by himself. When the cages were lifted, the female most often courted the male that had just mated. Similar studies have also turned up mate copying in Japanese madaka fish, sa@ mollies and swordtails. 'Me prevalence of copying suggests it must give the copier some edge in evolution, though exactly what this is remains unclear. One good reason for copying might be that it saves time choosing a mate-time that could be spent doing other things, such as eating or looking out for predators. Or it may be simply that dioosing a quality mate is tricky, and by watching what others do, you get more information on which to base this tough choice. This strategy fails, of course, ff the individual you copy knows less than you do. But the fact that young guppies tend to copy old ones rather than the other way around suggests that here, at least, copying may be a way of passing down accumulated wisdom. Birds and fish aren't renowned for their intelligence, though. So perhaps they rely on imitation because they tend not to do much thinking on their own. They follow the flock. They go with the flow. Would independent-minded human beings, with the power of reason and free choice, care about the choices other people make?

To find out, Dugatkin teamed up with psychologist Michael Cunningham, also at Louisville. They presented 166 female undergraduates with a report ostensibly written by five of their peers after a 20-minute interview with a man named Chris. In fact, the five women and Chris were all fictitious. The rqports ranked Chris's physical attractiveness on a scale of 1 to 10, and indicated how many of the women were interested in dating him. The reports rated Chns as either a 3 or a 10 in attractiveness. In addition, four, one or none of the women said she was inter-' ested in dating him. Once they had read the reports, the women undergraduates were asked how interested they might be, on a scale of 0 to 6, in dating Chri's. A high attractiveness rating raised the women's interest by just over a point on average compared with a low rating. But peer attention had a stronger effect, raising the average dating interest by one-and-a-half points. --fhe underlying assumption is that he must have something going for him," says Cunningham. 'If other people are attracted to him, he must have [email protected] they want.' Men are influenced by their peers too, but not nearly as much as women. Running the same experiment on a similar number of men with aR flie sexes reversed-but keeping the androgynous name, Chris-Dugatkin and Cunningham found that while men responded [email protected] to the attractiveness ratings, they relied less on other men to decide whether they were interested in Chris. High peer attention boosted their mean interest by less than a point in most of the experiments. The difference between men and women was even more pronounced when they were asked to rank their interest in marrying Chris. In this case, high peer attention raised the rating given by the men by barely half a point on average, whereas the women's interest jumped by two to three times as much, This is exactly what evolutionary theory might predict about mate copying. In most species females tend to be more picky than males. That's because they usually invest much more time and energy than males raising their offspring, so choosing the best mate pays big dividends. Males, on the other hand, can afford to be a bit more cavalier. "So males tend to use a smaller subset of infor-znation to determine what they are interested in," says Dugatkin. What exactly are women looking for in a mate? Dugatkin and Cunningham found that women (and men) were strongly influenced by the peer attention rating when forming opinions about Chris's various attributes. Regardless of the beauty rating, if four peers were attracted they said Chris must have a good sense of humour and good social skills, and, they said, Chris must be wealthy. These qualities are attractive because they suggest that Chris will be a good parent and provider. Studies suggest that wealth may be particularly important to women. Over a decade ago, David Buss, an evolutionary psychologist from the University of Texas at Austin, surveyed the mate preferences of some 10,000 people across 37 cultures. He found that women universally placed greater importance than men on good financial prospects as well as related factors such as status and ambition. More recent studies show that these factors weigh much less heavily with women in highly paid, high-status jobs, suggesting that the importance women place on wealth is linked to their own socioeconomic status. To see just how powerful an influence wealth could have on Chris's attractiveness, Cunningham and Dugatkin did another experiment in which they added a description of Chris as a humanities major with the potenfial to eam only about $20,000 a year. For half of the subjects, they added that Chris's parents had won $10 million in a sweepstake and set up a trust fund for Chris that would pay hitn $500,000 a year.

When all other variables were the same, wealthy Chris sparked slightly more interest among both females and males than poor academic Chris. But the impact was much smaller than Dugatkin had expected, possibly because the money said nothing about Chris's abilities. "One reason people would care about wealth is as an indicator of ambitiousness and personality overall," says Dugatkin. In some sense, then, being a rich person might be like being an orange guppy. Peer attention overrides orange colour in guppies, unless, Dugatkin has found, the guppy is very orange indeed. Then peer attention no longer gets the female to switch. In humans, what counts may be the ability to generate money rather than simply having lots of it. So the quesfion is, ff Chris had an ean-dng potential of $500,000 a year, Would that override the peer attenfion effect? It's certainly possible, Dugatkin says, but the experiment has stin to be done. What does any of this have to do with everyday life? "The phenomenon of groupies is relevant," says Buss. 'You get fairly geeky4ooking guys generating a sort of mass hysteria whidi might be a mate copying phenomenon." Chances are that few teenage girls swooned over John Lennon before the Beatles were famous. That sort of celebrity then leads directly to another kind of imitation. By the mid1960s most young men were trying to look hke the Beatles, then later Led Zeppelin and Depeche Mode. Today it's Eminem or David Beckham. 'Mate copying does helo us explain why there is a great deal of variation across societies and across time in what we find attractive about the opposite sex," says Dugatkin. Trends in clothing, hairstyle, even body piercin& are so volatile because of peer attention's snowball effect. As for the wedding ring effect, the hunt goes on. A few years ago, Cunningham and his colleagues tried an experiment in which women sat alone at a bar with a wedding ring clearly visible. But the results were inconclusive. "Choosing females may have been a tactical error," Cunningham says. "If she is an attractive enough female, whether she has a wedding ring or not, there is a high base rate of being approached." He has not yet tried the reverse experiment, with men waiting at the bar, in part because the base rate of women approaching men is quite low. Many more hours of observation would be required to detect an effect-as I can personally attest. "The way the ballet usually works is that the female makes eye contact and smiles," says Cunningham. "But it's still the guy who has to get up off his stool and move." So I'm getting off the stool and heading home. I am, after all, happily married.

The Imitation Factor by Lee Alan Dugatkin is published in January 2001 by The Free Press

Gene-Trapping Method Powers Discovery of New Brain-Wiring Signals

March 8, 2001- Researchers have developed a powerful screening method to identify genes that produce proteins that guide the wiring of the trillions of connections in the mammalian brain. The technique enables scientists to identify new genes and to determine which genes are responsible for defects in brain wiring that are observed during development. The scientists believe that this technique is likely to accelerate the discovery of new molecules involved in axon guidance.

Neurons wire themselves into networks by extending cable-like axons that grow toward specific targets in the nervous system. An axon's path toward a target neuron is steered by growth cones in the tip of the axon that receive cues about the best path to follow from chemical attractants and repellents secreted by cells in the nervous system. These attractants and repellents are collectively called axon guidance molecules.

In an article published in the March 8, 2001, issue of Nature, researchers led by Howard Hughes Medical Institute investigator Marc Tessier-Lavigne at the University of California, San Francisco and William C. Skarnes at the University of California, Berkeley, unveil their new technique and discuss some early applications of the method.