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31 aug 02

Sperm remember which way they swam

THEY turnout to be smarter than anyone thought: sperm can remember the twists and turns they've made. If human sperm turn in one direction, they'll tum in the opposite direction at the ne)d opportunity, Peter Brugger, a neurobiologist at University Hospital, Zudch, has found. 'It's certainly not cognitive memory," he says. But they must have some kind of memory.

This kind of behaviour, known as spontaneous alternation behaviour, is found in a wide ranp of creatures. To see whether human sperm cells exhibit it, Brugger recorded which way 714 healthy sperm cells turned when confronted with a left or right choice in a T-shaped channel. As expected, half the sperm went left and half went right. But in a maze that forced the sperm to turn right before they reached the T- junction, 58 percent tumed left (see below). Brugger, whose work vall appear in BehoWourat Brain Research, thinks the percent that "remember' which way to tum would be even greater if the maze were smaller. The sperm had to swim 10 times their body length after the forced turn, so some of them may already be 'forgetfing'. One simple explanation could be that each tum causes an asymmetry in the mechanism that controls a cell's tail, or flagellum. It then compensates by fuming in the opposite direction neid time. But it is also possible that the sperm are somehow communicating. "They could be flocking," Brugger says. To test this, he plans to repeat the experiment one sperm at a time. in the body, sperm fbilow a chemical trail to the egg. "But they may have choices [of which way to tliml when they get very close to the egg," says reproductive biologist Harry Moore of the University of Sheffield. Testing fbr alternation behaviour could be a way to check the health of sperm used for IVF, he adds. Duncan Graham-Rowe

2 Oct 02

Cancer scare hits gene cures

A second major setback for medicine's most pioneering treatment has split the scientific community. (ould a moratorium do more harm than good?


ROLLER COASTER is the only phrase for it. Soon after "patient X" was bom he was diagnosed as lacking vital immune defences due to a life-threatening genetic mutation. Six months later a pioneering treatment corrected the genetic defect and doctors pronounced him cured. Now, in a cruel reversal of fortune, the boy has leukaemia and is at the centre of the latest international row about the safety of gene therapy. Scientists and doctors are scrambling to digest the implications of last week's shock announcement that implanting the child with cells containing a healthy form of a defective gene may have led to his cancer. But already a confusing rift has opened up between the experts overseeing trials of the therapy in Britain and their counterparts in France and the US. British regulators say the potential benefits of the treatment are so great it would unethical to break off ongoing trials. French and American experts insist the only ethical course is to halt trails while scientists investigate whether the treatment really is responsible for the boy's leukaemia. They cannot both be right. But what is clear is that the illness - and the split over how to proceed - couldn't have come at a worse time for gene therapists. Long touted as the revolutionary key to treating inherited illnesses, gene therapy had only just recovered from the storm of criticism that followed the death of American teenager Jesse Gelsinger in the trial of a different type of gene therapy in 1999. Worse, the very treatment now being linked to leukaemia has been instrumental in restoring confidence, having produced a string of spectacular cures for other children suffering from "severe combined immunodeficiency". When Rhys Jones, one of four boys apparently cured by the therapy at Great Ormond Street Hospital in London, reached his second birthday just days before the leukaemia news broke, his mother described it as "a miracle". The disease, known as X-SCID, is linked to a gene on the X chromosome and leaves boys without any T cells, a type of white blood cell crucial to the immune system.

"Gene therapy has only just recovered from the storm of criticism that followed the death of American teenager Jesse Gelsinger"

The boys fall prey to even minor infections, and unless treated they normally die before their first birthday. Alain Fischer and his colleagues at the Necker Hospital in Paris treated patient X and lo others like him by taking bone marrow from their bodies and infecting it with a retrovirus carrying a normal copy of the defective gene. Stem cells in the bone marrow that took up the gene were then grown in culture and returned to the boy. After his treatment, doctors pronounced the boy cured and everything went well until he was two-and-a-half, when he contracted chickenpox. His white blood cell count soared to fight off the infection but never subsided afterwards. The cells continued to divide and he is now undergoing chemotherapy for leukaemia. "I think this event is directly linked to the gene therapy," Fischer told NewScientist. The French authorities stopped the trial immediately, and within hours the US Food and Drug Administration followed suit, halting three trials that were using retroviruses to insert genes. But in Britain, the government's Gene Therapy Advisory Committee (GTAC) voted to continue trials at Great Ormond Street. British experts argue that children with X-SCID would die if trials were stopped during the 12 to i8 months needed for the French investigation. They also say that leukaemia has always been regarded as a possible side effect of using retroviruses to genetically manipulate white blood cells, and that doctors in Britain made every effort to inform parents of the risk before any boys received the treatment. "In balancing the potential risks and benefits to these children we have decided it is ethically justifiable to go ahead," Norman Nevin, chairman of GTAC and a medical geneticist at Queen's University Belfast, told reporters last week. Not so, insists Arthur Caplan, one of the US's best known bioethicists at the University of Pennsylvania Medical School in Philadelphia. "You have to weigh the risks and benefits, and for some, leukaemia is a risk worth taking," he told New Scientist. "But to go ahead with trials not understanding exactly why leukaemia has arisen could turn risk into disaster." Yet even advocates of a moratorium see the swiftness of the American response as evidence of a "gun-shy" attitude to gene therapy among officials. The public uproar following Jesse Gelsinger's death forced a complete reappraisal of the procedures, safety and scope of gene therapy. Gelsinger was being treated for a liver disorder, using an adenovirus similar to those that trigger common colds. Although the cause of his death was and still is a mystery, the shock burst gene therapy's bubble, dispelling much of the hype that had surrounded it. But even after this second major setback, nobody is about to throw in the towel. "We're on a teaming curve and need to persevere with these methods," says Joseph Glorioso of the American Society of Gene Therapy.

"Leukaemia has always been regarded as a possible side effect of using retrovi ruses to genetically manipulate white blood cells"

And despite patient X's leukaemia, the clear benefits of the therapy in other cases will galvanise the best minds in the world to think of how to get round the problem, says Savio Woo, a gene-therapy expert at Mount Sinal School of Medicine in New York City. Woo supports a temporary moratorium but calls on people to get the situation in perspective. "Ten out of 11 patients responding is a miracle," he says.

Retrovirus blamed for giving boy leukaemia

THE finger of suspidon for the leukaemia that struck a young French boy recemng gene therapy is pointing squarely at the retrovirus used to treat his condition. Alain Fischer and his colleagues at the Necker Hospital in Paris worked with a retrovirus called the murine leukaemia virus (MLVI. To prevent the virus replicating in the body, they stripped out its reproductive genes. Then they used the modified virus to ferry a healthy copy af the boy's defective gene into cells taken ftm his bone marmw. The MLV infected the cells, dropping itself and the heathy gene into the boy's DNA. However, there is at present no way to control where such viruses "land". And in at least one batch of stem cells given to the boy, the added DNA ended up inside Lmo2, an oncogene on chromosomen that is implicated in leukaemia. The fear is that the virus switched on Lmo2 as well as the added gene (see Diagram). If so, the key question is: was this bad luck - a one-off event - or something that is likely to recur whenever gene therapists use retroviruses to correct genetic defects? Nicholas Lemoine cyf Imperial College in London, who edits the journal Gene Therapy, thinks that it is simply bad luck, but says we desperately need more data in order to understand the risks. The key is to find out how likely it is that rE,troviruses will land in and acthow ariy of the 300 or so known oncogenes in the human genome. "Three thousand indwiduals have had genes intmduced in some way or another," says Lemoine, "and a substantial number were treated with retroAruses.11 Most of the recipients of retroviruses have been children with an inherited condition called ADA deficiency. It means they can't make the enzyme adenosine deaminase, which is vital fbr immune funcaon. Savio Woo, director of gene therapy and molecular medicine at the Mount Sinai School of Medicine In New York City, reckons that hundreds of patients have received the viruses in the US. One fear Is that MtY may actually prefer to embed ltseff in genes linked with leukaemia. But that idea Is rejected by Adrian Thrasher and Bobby Gaspar, Immunologists with the gene therapy team In London at the Institute of Child Health at Great Ormond Street Hospital in London. They say the virus embeds itseff in different places in every patient Since there are more than 3 billion places where the therapeutic DNA could land, and because only 10 to loo cvf the infected bone marrow cells "take" when returned to the patierft, the chances of an oncogene being activated in those 10 to loo hits are slim indeed. But Thrasher is open to the idea there might be some lh(Yt spots" where the virus tends to settle. After all, he points out, HIV does show such preferences. All researchers contacted by New Scientist agreed that altering a single oncogene is seldom enough to cause cancer. Often, other genes need to be altered as well. Ken Campbell, clinical information officer at Britain's Leukaemia Research Fund, says that the young French boy may already have had a genedc predisposition fbr leukaemia and that the retro-Anis simply set the ball rolling. Whatever the answer, the best solution will be to control where therapeutic genes land. RetruAruses do exist that always embed themselm at the same spat in the genome, fbr example. But they're ncyt as effident at injecting genes as the those, such as MLY, that integrate unpredictably. Fischer says that it might be possible to add 'insulators" to the ends of the MLV genome in the hope cvf isolating it more fully ftm the surrounding genome. Another option might be to modify the retrovirus sothat it is only able to switch on the added gene. Andy Coghlan

3 aug 02

Wallaby nation

A STRANGE and disturbing force is at work in the wilds of Queensland, along the north-east coast of Australia. Venture out at dusk into the rugged hills encircling the city of Townsville, and in the failing light you'll glimpse the silhouettes of a dozen hunched creatures, each perched atop its own boulder, silent as a sentry. Not only do these hunchbacked "rock hoppers" look mysterious, something mysterious has happened to them too. Something has caused these marsupials to undergo genetic changes at a positively alarming rate. But what? An alien crash site oozing radiation? A covert operation to create a master marsupial? The explanation proposed by Rachel O'Neill, a geneticist at the University of Connecticut in Storrs, is only marginally less strange. She claims to have good evidence that the culprit was none other than a group of mischievous viruses. What's more, she says, the viruses wrought such profound genetic change that they gave birth to whole new species of rock hoppers - possibly in as little as a few decades. If she's right, Darwin is going to spin in his grave. It's a blow for the idea that it takes millions of years of natural selection to create a new species. And evolutionary biologists may have to accept that sometimes - just sometimes - an out-of-control genome might do the same job almost overnight. Until geneticists sat up and took notice, rock hoppers were best known for their tails - long even by wallaby standards. The seven species that live away from the Queensland coast boast a range of other novelties - from black mohawks and socks to pink patches on their heads that wash out in the rain, like logos on cheap T-shirts. By comparison, the eight species of rock hoppers that occupy the Queensland coast look pretty uniformlybrown. Like cult members, they are difficult to tell apart by looks alone - there are perhaps four people in the world who can do it. It was only when scientists systematically examined their DNA in the 1970s that they realised the creatures were separate species, and might just have something interesting to say about how new species emerge. After all, it's not every day you get eight identical-looking species living shoulder to shoulder in the same ecological niche. To understand O'Neill's pitch for how that might have happened, you first have to remember that it's not just genes that vary between species - it's the architecture of their chromosomes. The centromere, the bit that lets each pair of chromosomes link up before cell division, can change its position. The arms of each chromosome can be longer or shorter, and the DNA can be wound loosely or tightly around its protein spools, giving the chromosome its stripy appearance. Usually, there's not much structural difference between the chromosomes of closely related species. The llama in South America and the camel in Africa have identical-looking chromosomes, even though they've been separated by an ocean for 30 minion years. (They both have their own novel genes, however.) Similarly, a standard set Of 14 chromosomes has served most marsupials since their origins loo million years ago, and it persists almost unchanged in such far-flung relatives as wombats, bandicoots and Tasmanian devils. Even South American possums, which haven't brushed elbows with their Australian brethren for 8o million years, have the standard set. Macropods, such as kangaroos and wallabies, however, are a glaring exception. "There's a tendency among macropods to play Lego with their chromosomes, and in rock wallabies it's just gone completely haywire," says Mark Eldridge, a marsupial geneticist at Macquarie University in Sydney, and one of O'Neill's most enthusiastic supporters. Compare the allied rock hopper that lives around Townsville with the unadorned rock hopper, its neighbour to the south and you find some startling differences. Townsville's finest differs from its plain cousin in having chromosomes 3 and 4 rearranged so that their centromeres are at one end rather than in the middle, while chromosomes 6 and io have fused together. The chromosomes of the Mareeba rock hopper, which lives just to the north, are even more jumbled. It has two extra chromosomes fused together. in fact, judging by their chromosomes alone, the eight species of Queensland rock hoppers look as if they diverged from one another ioo million years ago, rather than 8oo thousand years ago, which is what changes within their gene sequences suggest. If this all sounds confusing, remember that the world of speciation research is characterised by incongruities. Biologists have, after all, yet to decide how to define a species. Normally, they use a mishmash of different approaches - categorising species according to their looks, such as red buttocks or webbed feet, whether or not they mate to produce fertile offspring, or according to their genetic makeup. But it's an imperfect art: some species, including the rock hoppers, look identical, while others - lo per cent of animals and 20 per cent of plants - can mate with different species to produce fertile offspring. The picture of how new species arise is also murky. The theory most often evoked is pure Darwin - populations of the same species take up residence in different ecological niches, where upon natural selection gradually hones them to fit their own niche until eventually they look and act differently from one another and a new species has emerged. Lake Nyasa in southeast Africa, is supposed to have spavined hundreds of species of cichlid fish this way. Some are adapted to hiding among rocks, others to living in sandy bays, some have mouths for eating scales off the right sides of fish, others for eating scales off the left sides, and so on. Another idea is that reproductive isolation drives speciation - a fragmenting forest sphts a population, preventing interbreeding until random mutations slowly but surely create distinct species. And then there's the theory that might best explain those identical-looking rock wallaby species in Queensland. Perhaps chromosome shuffling is creating new species by driving a reproductive wedge between two populations. The problem is that no one - until now - has devised a good explanation for what, exactly, might set the ball rolling. "When you look at the 4ooo species of mammals," says Stephen O'Brien, head of the laboratory of Genomic Diversity at the National Cancer Institute in Frederick, Maryland, "some species' chromosomes are shuffled five times more than others.' it's a puzzle we don't understand. One group of suspects that have been kicked around for years are retroviruses, which wheedle their genetic material into our own. It's a creepy thought, but the DNA of everything from cucumbers to cuttlefish is loaded with the genes of retroviruses that inveigled their way in millions of years ago. Once inside, they insert more copies of themselves into the host's DNA, even tuming up on other chromosomes. The copies also swap genes among themselves by a process called recombination. But they're sloppy operators. When a retroviral gene moves to a different chromosome, a piece of the host's own DNA often goes with it so that you end up with, say, a piece of the long arm of chromosome 2 stuck to the short arm of chromosome 7. And it's not just retroviruses: other types of "jumping" DNA - collectively called retroelements - are also suspected of scrambling chromosomes. Fortunately most living things have ways of silencing unwanted genes. Methylation, the simple addition of methyl groups to DNA, causes it to cofl tightly around the spools of the chromosomes. In so doing, it silences retroviral genes, stopping them from playing Mr Potato Head wfth the chromosomes. But what if they weren't always silenced, wondered O'Neill, could that explain how the rock hopper genomes became so jumbled? Enter Benny, the offspring of an unholy union between a tall swamp wallaby and a tubby tammar wallaby. Nobel laureate Barbara McClintock suggested 30 years ago that retroviruses might occasionally reshuffle chromosomes, and she thought the most likely place for this to happen was in the offspring of parents from two different species. They often have shuffled chromosomes, and the more distantly related the parents, the more shuffled they are. Tammars and swampies are distant cousins, so Benny's chromosomes are really weird. Many have centromeres that are io times as long as normal. In addition, part of an arm from chromosome 2 has-moved to chromosome 7, while part of the X chromosome is reversed. And when O'Neill analysed Benny's DNA she found, just as she predicted, that it was dramatically undermethylated. "It was very extreme, and quite shocking," she says. "We were looking for a needle in a haystack, and we accidentally just sat on it. This wasn't the only revelation, either. When O'Neill sequenced the chromosomes with long centromeres, she found they were actually made of pieces of retrovirus DNA repeated thousands and thousands of times, which she described in a landmark paper (Nature,vOI393,p68).

Do the virus shuffle With that evidence under their belts, O'Neill and Jennifer Marshall Graves, her PhD advisor at La Trobe University in Melboume, fthed in the gaps in their theory for how chromosomal jumbles could occasionally create new species. First, of course, members of different but closely related species must mate and produce a youngster. Then, suppose one such hybrid fails to methylate its DNA correctly right at the start when it's just a single fertilised cen. Seizing their chance, the retroviruses awaken and make thousands of copies of themselves - thoroughly scrambling the chromosomes before the hybrid embryo reaches the size of a pea. Once that hybrid reaches maturity ft just needs to flnd a secluded spot where it can breed with a few animals from one of the parent species. Within a few generations, its descendants wifl have the same chromosomes, including some of the original hybrid's shuffled ones, and a new species is created. "We've always felt evolutionary change would be very, very slow," says Marshall Graves, who now splits her time between the Australian National University in Canberra and the University of Melboume. But Benny contradicts all that, she says: "We find major changes that probably occurred very rapidly after fertflisation. Something that we thought might take 50 million years might take 5 minutes instead.' Their idea may sound overelaborate, but in rock hoppers at least the theory seems to be home out by geography. The Queensland rock hoppers are crammed Into a coastal strip of forests where there would be ample opportunity for the ancestral species to interbreed. By contrast, the rock hoppers scattered around the rest of the huge Australian continent probably had little opportunity for such liaisons, and their chromosomes are less shuffled and more like the standard issue. "You see the same thing over and over again," says O'Neill. Each of the two main species of Australian grasshopper, for example, has its own unique set of chromosomes, but where their habitats overlap there are plenty of grasshoppers sporting newly shuffled chromosomes. And in northern Italy, a new strain of house mouse with jumbled chromosomes has appeared in the last 20 years - once again, at the intersection between two other species' habitats. To the uninitiated, of course, mating two different species of animals might seem an easy way to create a third. But while plants do it sometimes, it's usually a dead end for animals, which is one of the limitations of the new theory. Although animal species can produce fertile offspring when they interbreed with closely related species, those hybrids are usually less fertile than the parent species, so their genetic contribution quickly disappears from the population. "These new hybrid entities probably form fairly often," says Loren Rieseberg, a geneticist at Indiana University in Bloomington. "But most of them cannot survive [competition] with the parental species, and so they get swallowed back up by the parental species.' To get around that problem, O'Neill and Marshall Graves envisage a hybrid like Benny finding itself in an isolated spot where it only has to compete with a few other animals. That scenario would seem reasonable for rock hoppers, which dot the countryside in small groups, wherever there's a boulder heap. But reduced fertility is not the only reason why some researchers doubt that genome scrambling accounts for many new animal species. According to Reinald Fundele, a developmental biologist at the Max Planck Institute for Molecular Genetics in Berlin, the offspring of two different species don't necessarily have undermethylated or scrambled chromosomes. He's examined crosses between camels and llamas, horses and donkeys, and two mouse species, and found no evidence of either. In fact, says Fundele, the undermethylation route to scrambling chromosomes maybe impossible in non-marsupials. For them, methylation is so critical to early development that the embryos probably wouldn't survive. O'Neill, however, has a comeback. She claims you just have to look harder in non-marsupials for signs of undermethylation. Using refined techniques, she's examined her own mouse crosses and found slight reductions in methylation that would escape the cruder detection techniques used by other researchers, such as Fundele. The results are preliminary, but these mice also have chromosomal shuffles. What's more, natural selection might better explain the speciation driven by different ecological niches, such as the cichlids in Lake Malawi, but her theory does a better job of explaining those species that emerge in similar niches but with dissimilar chromosomes, such as the rock hoppers, certain look-alike South American field mice, which shlep around anywhere from 10 to 42 chromosomes, and the muntjacs or Barking deer of South-East Asia. "This is a potentially very interesting mechanism where there isn't necessarily any natural selection driving the differences," says Andrew Hendry, an evolutionary biologist at University of Massachusetts in Amherst. Eldridge agrees. "The rock wallabies are doing something very different from classic examples of speciation. It's the genome that's driving it - an out-of-control genome.' One thing is certain: the Benny effect has people buzzing. A creationist website even touts it as evidence that evolution could fit into the lo,ooo years demanded by the Bible. "I was impressed at the creativity of that argument," quips O'Neill, "and almost embarrassed 0 Douglas Fox is a science writer living in Northern California. Further Reading: "chromosome heterozygosity and de novo chromosome rearrangements in mammalian interspecies hybrids" by Rachel Waugh O'Neill, Mark Eldridge and jennifer Marshall Graves, Mammalian Genome, vol 12, p 256 (2001)