Gene therapy may switch off Huntington's
10:32 13 March 03 Exclusive from New Scientist Print Edition

Using gene therapy to switch off genes instead of adding new ones could slow down or prevent the fatal brain disorder Huntington's disease. The method, which exploits a mechanism called RNA interference, might also help treat a wide range of other inherited diseases.
Silencing faults
Silencing faults

"When I first heard of this work, it just took my breath away," says Nancy Wexler of Columbia University Medical School, who is president of the Hereditary Disease Foundation in New York. Though the gene-silencing technique has yet to be tried in people, she says it is the most promising potential treatment so far for Huntington's.

It involves a natural defence mechanism against viruses, in which short pieces of double-stranded RNA (short interfering RNAs, or siRNAs) trigger the degradation of any other RNA in the cell with a matching sequence. If an siRNA is chosen to match the RNA copied from a particular gene, it will stop production of the protein the gene codes for (see graphic).

Huntington's is caused by mutations in the huntingtin gene. The resulting defective protein forms large clumps that gradually kill off part of the brain. Studies in mice have shown that reducing production of the defective protein can slow down the disease, and Beverly Davidson at the University of Iowa thinks the same could be true in people.

"If you reduce levels of the toxic protein even modestly, we believe you'll have a significant impact," she says. Late in 2002, her team showed that it is possible to reduce the amount of a similar protein by up to 90 per cent, by adding DNA that codes for an siRNA to rodent cells engineered to produce the protein.


Disease-causing genes

The team was the first to use gene therapy to deliver such a payload, and they have now done the same with the huntingtin protein itself. Completely silencing the gene in people with the disease is not an option because brain cells may not survive without the protein. But we have two copies of most genes, and usually only one is defective in people with Huntington's.

Working on a similar disease using human cells, Davidson and her colleague Henry Paulson have now shown you can make an siRNA that recognises and silences only the mutant gene.

They could not target the disease-causing mutation itself because, as in Huntington's, the mutation merely makes a long stretch of repeats even longer, without actually altering any particular short sequence. But they did find another difference, a change in a single DNA letter that appears in 70 per cent of defective genes.

Adding an siRNA that matches this telltale sequence reduced expression of the defective protein by over 80 per cent, while production of the normal protein was hardly affected, Davidson told a gene therapy conference in Banff, Canada, last week. The hunt is now on for similar mutations in the huntingtin gene itself. One promising candidate has been discovered in about 40 per cent of disease-causing genes.

The same approach could probably be used for many other genetic disorders. Even if both copies of a gene are faulty, a healthy copy of the gene could be added alongside an siRNA that turns off both defective copies.


Bob Holmes, Banff

Radioisotopes reveal victim's life and death
19:00 12 March 03 Exclusive from New Scientist Print Edition

Murder detectives finally have a reliable way to determine how long a victim has been dead from their bones, as well as glean valuable information about where the person lived.

Stuart Black, an environmental geochemist at the University of Reading, is pioneering a technique similar to carbon dating, but that uses isotopes of other elements. He has just finished his first case.

From the charred remains of a man who was repeatedly stabbed and then set on fire, he determined that the victim was probably from the former Soviet Union and had been dead about a week.

"While that doesn't give us a name and address, it helps immensely," says Detective Superintendent David Hankins of the Cambridgeshire police. "Dr Black has given us an incredible amount of information." Police are so impressed, Black's lab is already working on two other murder cases, and three more are awaiting analysis.


Decay rate

To date remains, forensic scientists normally rely on studies of how bodies decay in different climates (New Scientist print edition, 6 January 2001). But the temperature and moisture conditions where the corpse was left are often unknown, making these methods imprecise.

"The error is unquantifiable. It relies on pathologists saying 'oh, I've seen a bone like that before, and it was about this old'," says Black.

Instead, Black looks at the decay of radioactive isotopes. Carbon dating has long been used by archaeologists looking at bones that are centuries old, but is little use for younger bones. To date more recent remains, Black is using isotopes with shorter half-lives than carbon-14. He has found that the most useful are lead-210 and polonium-210, with half-lives of 22 years and 134 days respectively.

These and other elements entering our bones are primarily from food, so Black can also use his measurements to sketch the victim's diet. A depletion of certain elements will reveal if the person was a vegetarian, for example.


Regional diet

Black has also refined a way of using various stable isotopes of lead to indicate where the victim lived in the last decade of their life. This lead is breathed in with air, and the amount depends on factors such as local geology and the kind of petrol used by cars in the area.

Knowing where the victim lived is useful for police, but also means Black can take regional differences in diet into account, to pin down the age of the bones even more accurately. In Britain, he consults the Food Standards Agency's database to check how much radioactive lead and polonium is in different foods.

Black originally tested the technique on a sample of bones from 25 elderly women from a small Portuguese town. He found he could pin down the date of death to within two years for women who had been dead 50 years. That precision probably reflects the fact that they had very similar diets, says Black. To work out how accurate the technique is in other cases, he says we need to find out how variable these radioactive elements are within other populations.

But even with a big margin of error, the method could still sort out the surprisingly common confusion about whether bones are years or centuries old, according to forensic scientist Kenneth Pye, who heads a consultancy in London. "You get heaps of remains found in London building sites. These are treated as crime scenes, but they often turn out to be medieval."


Nicola Jones

World's first brain prosthesis revealed
19:00 12 March 03 Exclusive from New Scientist Print Edition

The world's first brain prosthesis - an artificial hippocampus - is about to be tested in California. Unlike devices like cochlear implants, which merely stimulate brain activity, this silicon chip implant will perform the same processes as the damaged part of the brain it is replacing.

The prosthesis will first be tested on tissue from rats' brains, and then on live animals. If all goes well, it will then be tested as a way to help people who have suffered brain damage due to stroke, epilepsy or Alzheimer's disease.

Any device that mimics the brain clearly raises ethical issues. The brain not only affects memory, but your mood, awareness and consciousness - parts of your fundamental identity, says ethicist Joel Anderson at Washington University in St Louis, Missouri.

The researchers developing the brain prosthesis see it as a test case. "If you can't do it with the hippocampus you can't do it with anything," says team leader Theodore Berger of the University of Southern California in Los Angeles. The hippocampus is the most ordered and structured part of the brain, and one of the most studied. Importantly, it is also relatively easy to test its function.

The job of the hippocampus appears to be to "encode" experiences so they can be stored as long-term memories elsewhere in the brain. "If you lose your hippocampus you only lose the ability to store new memories," says Berger. That offers a relatively simple and safe way to test the device: if someone with the prosthesis regains the ability to store new memories, then it's safe to assume it works.


Model, build, interface

The inventors of the prosthesis had to overcome three major hurdles. They had to devise a mathematical model of how the hippocampus performs under all possible conditions, build that model into a silicon chip, and then interface the chip with the brain.

No one understands how the hippocampus encodes information. So the team simply copied its behaviour. Slices of rat hippocampus were stimulated with electrical signals, millions of times over, until they could be sure which electrical input produces a corresponding output. Putting the information from various slices together gave the team a mathematical model of the entire hippocampus.

They then programmed the model onto a chip, which in a human patient would sit on the skull rather than inside the brain. It communicates with the brain through two arrays of electrodes, placed on either side of the damaged area. One records the electrical activity coming in from the rest of the brain, while the other sends appropriate electrical instructions back out to the brain.

The hippocampus can be thought of as a series of similar neural circuits that work in parallel, says Berger, so it should be possible to bypass the damaged region entirely (see graphic).


Memory tasks

Berger and his team have taken nearly 10 years to develop the chip. They are about to test it on slices of rat brain kept alive in cerebrospinal fluid, they will tell a neural engineering conference in Capri, Italy, next week.

"It's a very important step because it's the first time we have put all the pieces together," he says. The work was funded by the US National Science Foundation, Office of Naval Research and Defense Advanced Research Projects Agency.

If it works, the team will test the prosthesis in live rats within six months, and then in monkeys trained to carry out memory tasks. The researchers will stop part of the monkey's hippocampus working and bypass it with the chip. "The real proof will be if the animal's behaviour changes or is maintained," says Sam Deadwyler of Wake Forest University in Winston-Salem, North Carolina, who will conduct the animal trials.

The hippocampus has a similar structure in most mammals, says Deadwyler, so little will have to be changed to adapt the technology for people. But before human trials begin, the team will have to prove unequivocally that the prosthesis is safe.

Collateral damage

One drawback is that it will inevitably bypass some healthy brain tissue. But this should not affect the patient's memories, says Berger. "It would be no different from removing brain tumours," where there is always some collateral damage, says Bernard Williams, a philosopher at Britain's University of Oxford, who is an expert in personal identity.

Anderson points out that it will take time for people to accept the technology. "Initially people thought heart transplants were an abomination because they assumed that having the heart you were born with was an important part of who you are."

While trials on monkeys will tell us a lot about the prosthesis's performance, there are some questions that will not be answered. For example, it is unclear whether we have any control over what we remember. If we do, would brain implants of the future force some people to remember things they would rather forget?

The ethical consequences of that would be serious. "Forgetting is the most beneficial process we possess," Williams says. It enables us to deal with painful situations without actually reliving them.

Another ethical conundrum concerns consent to being given the prosthesis, says Anderson. The people most in need of it will be those with a damaged hippocampus and a reduced ability to form new memories. "If someone can't form new memories, then to what extent can they give consent to have this implant?"


Duncan Graham-Rowe

American Physical Society,
Austin, Texas, March, 2003

Better breast cancer screens?
3D X-ray mammograms could reduce false positives.
11 March 2003

ED GERSTNER

Breast cancer is highly treatable if detected early.
© SPL

A new three-dimensional breast imaging technique could increase the detection of early-stage cancers and reduce the number of unnecessary biopsies.

Called full-field digital mammography tomosynthesis, the technique is the first to use X-rays to produce 3-D breast scans, Jeffrey Eberhard of GE Global Research told last week's American Physical Society meeting in Austin, Texas.

Conventional mammography projects X-rays through the breast onto a sheet of photographic film or detector screen. Tumours, being more dense than most healthy tissues, show up as a shadow on the exposed film or screen.

This detects only 65-70% of breast cancers - small tumours can be obscured by other breast structures. Moreover, only 10-20% of women who have a biopsy turn out to have cancer, as overlapping images of healthy bits of tissue can sometimes look like a possible tumour.

Instead of keeping the X-ray source stationary, Eberhard's team scans the breast in an arc and collects a sequence of 10 to 20 images in a digital detector. They then use a computer to turn these images into a series of 2-D cross-sections. In this way they build up a much sharper and more detailed picture of the breast tissue.

Several 3-D imaging techniques are currently being developed - including ultrasound and magnetic resonance imaging. But X-rays could prove cheaper, faster and give better resolution.

"Even relatively small clinics have standard X-ray mammography equipment", says Eberhard. Tweaking it for 3D, he suggests, "would enable them to move into 3-D without the big investment of magnetic resonance imaging".

Preliminary clinical studies involving 200 patients at Massachusetts General Hospital look promising, Eberhard told the meeting: "People are pretty excited about this technology."

Each year in the United States alone, 44 million women are screened for breast cancer and 46,000 women die of the disease. In contrast to many other cancers, breast cancer is highly treatable if detected early.

Mammography tomosynthesis is also being looked into for lung-cancer screening, as it uses a 25% lower X-ray dose than conventional computer tomography scanning.

Ed Gerstner is the editor of the Nature Publishing Group's Physics Portal and Materials Portal.


© Nature News Service / Macmillan Magazines Ltd 2003

DNA: Beyond the double helix

The world of science is gearing up to celebrate the 50th anniversary of Watson and Crick's seminal paper. But there's more to DNA than the pair's iconic structure. Helen Pearson profiles a truly dynamic molecule.
6 February 2003

HELEN PEARSON

This story is from the news features section of the journal Nature

Every day, as a young postdoc, Susan Gasser gazed at a twisted wire skeleton of DNA that was collecting dust in her supervisor's office - a sculptural homage to Jim Watson and Francis Crick's epoch-making paper on the double helix1.

But Gasser now heads a molecular biology laboratory at the University of Geneva, whose members see DNA in a very different light. By shooting microscopic movies of clumped DNA in the heart of living cells, Gasser and her colleagues have shown the molecule to gyrate like a demonic dancer. For Gasser, the iconic image of DNA as a static double helix is somewhat passé: she's now fascinated with the significance of its endless acrobatics.

"The way I think about DNA is different," says Gasser, who is not alone. Watson and Crick transformed biology by revealing the three-dimensional structure of DNA - and in so doing, set the stage for a lasting obsession with its sequence of chemical letters. But 50 years on, researchers are realizing that DNA has a fascinating life in three dimensions - and the fourth dimension of time - that makes it far more than a simple string of code.

The way I think about DNA is different
Susan Gasser
University of Geneva

Today's studies paint a more complete picture of DNA by examining the molecule as it coils in the cell's nucleus. In this context, structural biologists now believe that DNA is frequently unfaithful to its famous structure. The double helix, it has emerged, regularly morphs into alternative shapes and weaves itself into knots.

Cell biologists, meanwhile, are exposing the surprisingly dynamic life of the molecule after it crumples up into chromosomes. The latter form fleeting liaisons with proteins, jiggle around impatiently and shoot out exploratory arms. The nucleus, like DNA, was once thought to be fairly static, recalls structural biologist Alexander Rich of the Massachusetts Institute of Technology in Cambridge. "Now we know it to be a very lively place," he says.

Some researchers believe that these mysterious movements may be just as important as the genetic sequence itself in deciding which genes are switched on and off. They even have tantalizing evidence that a failure to coordinate this subcellular waltz could underlie some human diseases. Half a century may have passed since the double helix made its debut, but in some ways, scientists have only just begun to understand this miraculous molecule as it twirls in time and space.

The realization that the double helix isn't the be-all and end-all of genetics stems partly from the discovery by structural biologists of DNA posed in other weird and wonderful shapes. More than two decades ago, Rich first determined the structure of one such variant, called Z-DNA2. Although still a double helix, this molecule swirls in the opposite orientation to Watson and Crick's right-handed coil, like a telephone cord after a kink. But because it was identified in test-tube conditions, the left-handed Z-DNA wasn't considered a significant player in cellular life.

Only recently have researchers found evidence that Z-DNA might be vital in controlling gene activity. In 2001, a team led by Keji Zhao of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, showed that part of the regulatory sequence of an immune-system gene must flip into Z-DNA before the gene can be activated3.

Zhao and other biologists now believe that similar stretches of transiently existing Z-DNA, of which there are perhaps 100,000 in the human genome, may help to switch on genes by making them more accessible to proteins, such as transcription factors, that stimulate gene activity. Building on this idea, Rich already has evidence that the vaccinia virus, which is related to smallpox, may specifically hijack vulnerable Z-DNA, thereby crippling human cells. In unpublished work on mice, he has found that preventing a viral protein from binding to Z-DNA weakens an infection.

Besides the helix's jumps and twists, DNA may also morph into shapes that are a world away from the familiar spiral. Last year, Stephen Neidle of the Institute of Cancer Research in London unveiled one such form that is adopted at the ragged ends of chromosomes, known as telomeres, where the two sister strands give way to a lone string. Using X-ray crystallography, he showed that this single strand can weave itself into a tidy propeller-like loop, which may help to prevent the molecule from fraying away4. "It goes well beyond the linear double helix," says Neidle, who is now at the University of London School of Pharmacy.

Neidle's propeller-like structure belongs to a class of departures from helical forms of DNA known as 'G-quadruplexes', which occur in sequences that are rich in guanine, one of the four letters of the genetic code. Another member of the class may prevent genes from being switched on. Last summer, Laurence Hurley of the University of Arizona in Tucson showed that one type of G-quadruplex forms next to the potent cancer-causing gene c-MYC. Negating this structure by mutating its genetic sequence boosted the gene's activity5. Hurley suspects that the shape wards off gene-activating proteins, and he is now searching for drugs that could help to stabilize G-quadruplexes and thus serve as anti-cancer agents.

Even in its standard, helical form, DNA is throwing up surprises. The molecule has long been known to form intimate relationships with proteins that help it to fold, and trigger or subdue gene activity. Until recently, these liaisons were thought mostly to be fixed, or to change only slowly with time. But this idea has collapsed, as improved cellular imaging technology has allowed biologists to watch living cells in real time.

The resulting videos exposed an unexpected hubbub in the activity of proteins buzzing around DNA. "It changed the way we thought about the nucleus," says Tom Misteli of the National Cancer Institute in Bethesda. "The word 'static' is disappearing from our vocabulary."

Misteli's is one of several groups that took the lid off this nuclear ants' nest, using a technique called fluorescence recovery after photobleaching (FRAP). The researchers blasted lasers at live cells containing fluorescent proteins, bleaching out the fluorescence in a small spot of the nucleus. To Misteli's surprise, glowing proteins from elsewhere in the nucleus rushed in to fill the void6.

Many researchers now believe that almost all nuclear proteins are scuttling constantly back and forth, moving at speeds that would allow them to traverse the nucleus in as little as five seconds. Even histone H1, a protein that was thought to sit cuddled in the arms of DNA, now appears to attach and detach itself every minute or so7, 8. Although one might think that such turmoil would detract from the orderly functioning of DNA, Misteli speculates that this swirl of proteins helps cells to regulate gene activity. It may allow genes to sample constantly from the soup of transcription factors and other regulatory proteins that are milling around the nucleus.

Food for thought

This conjures up a picture of DNA as a tangle of noodles swilling lazily around in a nourishing molecular soup. But in fact, stuffing some two metres of DNA into a nucleus one-millionth of this width requires some exquisitely careful packing. DNA wraps itself around histone proteins to form a nodular structure called chromatin, which in turn coils up like an overtwisted string into globular chromosomes.

Over the past few years, researchers have come to realize that chromosomes, which seem to be carefully arranged in the nucleus, may be positioned so that those that are most important to the cell gain preferential spots. Wendy Bickmore and her colleagues at the UK Medical Research Council's Human Genetics Unit in Edinburgh have shown that human chromosome 18, which carries only a handful of active genes, is relegated to the edge of the nucleus, whereas the gene-packed chromosome 19 sits near the middle9. Other researchers have revealed that this organization is preserved in the cells of primates from humans to monkeys10.

The fact that this chromosomal positioning has been maintained over some 30 million years of divergent primate evolution suggests that the order in which chromosomes are packed in the nucleus is functionally important - but exactly what purpose this packing serves remains unclear. Some scientists suggest that pushing a chromosome to the edge of the nucleus may help to hive it off from gene-activating machinery and keep unwanted genes gagged. But Bickmore suspects that peripheral chromosomes may act as defensive 'padding' for the nucleus' valuable genetic cargo, shielding DNA from mutagenic chemicals. "It might be to protect the most important part of the genome from damage," she speculates.

Studies of chromosomal positions used to involve dead cells fixed on microscope slides. But over the past few years, it has also become possible to watch chromosomes in action, thanks largely to a technique for filming a gene's location in living cells that was developed by Andrew Belmont's team at the University of Illinois at Urbana-Champaign. Belmont engineered mammalian cells to carry multiple copies of a bacterial DNA sequence, which can be tagged by a fluorescent bacterial protein11.

Using Belmont's system, researchers have shown chromosomes to be constantly in motion. Chromosomes in cells from yeast to mammals all appear to shimmy around by diffusion within their confined territories, wiggling frantically from second to second12. Gasser is one of the biologists who has watched these antics, and believes that the shuddering motion helps Misteli's scudding proteins to find their targets in the vast genome. "Before, it was almost inconceivable how a protein would find its binding site," she says.

Time-lapse images show how a yeast chromosome roams around the nucleus.
© T. Laroche / Science

Chromatin also pulls off some more impressive stunts. Belmont, for example, has engineered mammalian cells to carry a large array of bacterial genes that can be switched on, and tagged, by a fluorescent activating protein. Within several hours of being turned on, the genes unfurl from dense spots of chromatin into diffuse fibres13. Applying the same trick to a smaller cluster of bacterial genes caused its chromatin to move a good distance from the edge of the nucleus towards its interior14.

Meanwhile, Amanda Fisher and her colleagues at Imperial College, London, have shown that chromatin's wanderings may help to lock unwanted genes in an 'off' configuration. In developing immune cells, Fisher demonstrated that chromatin carrying genes that are no longer needed moved close to regions of inactive DNA called heterochromatin, which is thought to suppress neighbouring genes. If this relocation did not occur, the genes reactivated15.

Cause and effect?

But Fisher is the first to point out the problem with such observations: they may link DNA movement to changes in gene activity, but they do not prove that one causes another. Some scientists maintain that a wandering genome might simply be a passive consequence of the hustle of proteins around it. But researchers led by John Sedat of the University of California, San Francisco, have provided evidence to the contrary. They studied a mutant version of an eye-colour gene in the fruitfly Drosophila, which tends to manoeuvre itself next to genetically mute heterochromatin on the outskirts of the nucleus. The researchers found that, unusually, the dysfunctional gene drags with it a normal copy of the gene on its partner chromosome - and that, when this happens, the normal copy is also switched off16.

With such tantalizing signs that chromosomal and chromatin movements may spark or silence gene activity, some scientists are asking whether disruptions in location could trigger disease. Misteli, for example, has gathered evidence that in mouse lymphoma cells, chromosomes 12, 14 and 15 huddle closer together than normal17. He suspects that their proximity might be what predisposes the cells to become cancerous, by facilitating the abnormal exchange of chromosome regions that can trigger uncontrolled cell division.

Such work implies that patients with a susceptibility to cancer might be diagnosed on the basis of the positions of their chromosomes within the nucleus. With this in mind, Robert Singer of the Albert Einstein College of Medicine in New York has developed a technique that takes a snapshot of the positions of active genes in a single cell. This could be used, for example, to help pathologists to examine a breast biopsy or a suspect skin mole.

The team created 11 fluorescent tags of different colours, and washed them over human cells. Each sticks to the molecules produced by one specific gene, revealing how active it is and its location in the nucleus18. Looking ahead, others are honing this technique in order to watch human genes in action. They hope to combine multi-coloured tags that will flag not just DNA, but also the messenger RNA molecules churned out by active genes, and the proteins that they encode.

Such developments promise to bring further insights into DNA's enigmatic life in space and time - marking a new chapter in the molecule's history. "Watson and Crick must have thought that sequence was everything," reflects Peter Cook, who studies the structure and function of the cell nucleus at the University of Oxford, UK. "But life is much more complicated than that."
References

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# Parkinson, G. N., Lee, M. P. H. & Neidle, S.. Nature, 417, 876 - 880, (2002).
# Siddiqui-Jain, A., Grand, C. L., Bearss, D. J. & Hurley, L. H.. Proceedings of the Nationall Acadamy of Sciences USA, 99, 11593 - 11598, (2002).
# Phair, R. D. & Misteli, T.. Nature, 404, 604 - 609, (2000).
# Lever, M. A., Th'ng, J. P. H., Sun, X. & Hendzel, M. J.. Nature, 408, 873 - 876, (2000).
# Misteli, T., Gunjan, A., Hock, R., Bustin, M. & Brown, D. T.. Nature, 408, 877 - 881, (2000).
# Croft, J. A. et al. Journal of Cell Biology, 145, 1119 - 1131, (1999).
# Tanabe, H. et al. Proceedings of the National Academy of Sciences USA, 99, 4424 - 4429, (2002).
# Robinett, C. C. et al. Journal of Cell Biolofy, 135, 1685 - 1700, (1996).
# Marshall, W. F.. Current Biology, 12, R185 - R192, (2002).
# Tumbar, T., Sudlow, G. & Belmont, A. S. J.. Cell Biol., 145, 1341 - 1354, (1999).
# Tumbar, T. & Belmont, A. S. J. Nature Cell Biology, 3, 134 - 139, (2001).
# Brown, K. E., Baxter, J., Graf, D., Merkenschlager, M. & Fisher, A. G.. Molecular Cell, 3, 207 - 217, (1999).
# Dernburg, A. F. et al. Cell, 85, 745 - 759, (1996).
# Parada, L. A., McQueen, P. G., Munson, P. J. & Misteli, T.. Current Biol, 12, 1692 - 1697, (2002).
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© Nature News Service / Macmillan Magazines Ltd 2003

Gauging age by the smell of urine

00:01 12 March 03

NewScientist.com news service


Mice can recognise their elders by the smell of their urine, a new study shows. This unusual skill could turn out to be very important to mice, as it suggests a mechanism behind one theory of mate choice.

The "good genes" hypothesis proposes that females who prefer older mates do so because longevity may indicate hardy genetic stock. The preference for older mates has been documented in several species.

For example, both sexes of meadow voles are attracted to the smell of older members of the opposite sex.

"There's lots written about the genetic theory behind this," says research leader Gary Beauchamp, at the Monell Chemical Senses Center in Philadephia, Pennsylvania. "But there's a lack of data showing how the animals might detect age or the molecules involved."


Smelly creatures

Beauchamp and his colleagues chose to study age-related smells in mice, because while they have not yet been shown to prefer older mates, they do rely heavily on smells for a variety of social interactions.

The researchers compared urine from reproductively active mice from two age groups: three to 10 months and greater than 17 months. "That would be like comparing men in their 20s and men in their 50s," he says.

Next they were able to train "sensor" mice to find the older or younger urine at the end of a Y-shaped tunnel, suggesting some odorous compound did distinguish old from young urine.

Some chemical detective work identified phenylacetamide and indole as possible suspects, both of which were found to be elevated in the urine of the older mice. And when young urine was spiked with these two chemicals, the sensor mice misidentified it as old urine.

Hard to fake

The physiological significance of the chemicals is not clear, although phenylacetamide is associated with the function of immune cells called granulocytes that proliferate with age.

Intriguingly, since aging is also associated with a decline of the immune system, this would be a change that would be hard for younger animals to fake.

"But I suspect it would have to be sensed in the context of other chemicals as well," notes Beauchamp. "Otherwise animals would also be attracted to sick mates."

Beauchamp now plans to track down the biological origin of the chemicals and test whether their levels also change with aging in other animals. These will include humans, in which young women have been noted to prefer successful older men.

Journal reference: Proceedings of the Royal Society of London B (DOI: 10.1098/rspb.2002.2308)


Philip Cohen

Antibodies cripple prions
Therapy looks best yet to tackle brain disease.
6 March 2003

HELEN PEARSON

Prion diseases are caused by the twisting and clumping of normal brain proteins.
© SPL

The possibility of using antibodies to treat variant Creutzfeldt-Jakob disease (vCJD) receives a boost this week, with the first promising results from an animal trial.

The lethal brain condition - which is a human version of mad cow disease - occurs when healthy proteins called prions become twisted and clump together. Probably caught from eating infected beef, there is currently no known cure for the condition.

A team of London researchers injected mice with antibodies that latch onto prions. The animals, who had another form of prion disease called scrapie, stayed healthy for at least two years, rather than dying by the time they reached seven months1.

This is the first therapy to show such promise against animal symptoms. "It's a quantum leap in the efficacy of any treatment against prion disease," claims study leader Simon Hawke of Imperial College.

Winning battle

The new results come days after another encouraging report about prion diseases: that the predicted vCJD epidemic may be smaller than was feared. New figures2 show that the number of new British cases fell from a peak of 28 in 2000, to 17 in 2002.

Even so, the future death toll may lie anywhere between 10 and 7,000 in Britain alone, according to recent predictions3. "It's an untreatable, universally fatal disease," says prion researcher Neil Cashman of the University of Toronto in Canada.

Besides therapy with antibodies, anti-prion drugs are also being developed. In 2001, one British vCJD patient was reported to have made an astonishing recovery during a trial of quinacrine, an anti-malarial, and chlorpromazine, an anti-psychotic.

But the woman has since died - and the final trial results are expected to be disappointing. "There's no slam-dunk in chemotherapy," says Cashman. He agrees that antibodies now look to be the most hopeful therapy.

Hawke's team injected their antibody into mice that were 30 days into the disease - before symptoms occur, but at a time when prions are multiplying ferociously. The antibodies probably prevent normal prions folding into the misshapen, disease-causing form.

Before the antibodies can be tested in people, the mouse version will need to be altered - or 'humanized' - so that it can be tolerated by the body. It might also have to be shot straight into the brain, because it cannot diffuse there from the blood.

Hawke hopes that his result will also spur the development of antibodies against other diseases caused by abnormally folded proteins. Strings of protein clog the brains of Alzheimer's patients, for example.

Doctors are wary of using antibodies against Alzheimer's after a human trial of a vaccine that aimed to raise antibodies against the brain plaques backfired in 2001. Several patients in the study developed brain inflammation. "This should give [renewed] impetus," says Hawke of the new findings.

Mice catch cruise-ship virus
Cousin of Norwalk-like virus could help fight outbreaks.
7 March 2003

HELEN PEARSON

Last year, a humble virus achieved notoriety when it ruined Americans' dream vacations. Now scientists have begun to understand the culprit by recreating the infection in mice.

Late last year, outbreaks of Norwalk-like virus sent cruise ship passengers to their cabins with vomiting and diarrhea. Military camps, hospitals, even church picnics, regularly fall foul of the pathogen that each year affects around 23 million people and kills 300 in the US alone. It jumps from infected faeces to the mouth via food or contaminated surfaces.

Now Herbert Virgin and his colleagues have identified a cousin of Norwalk-like virus that lurks in mice, which should make infection far easier to study. "We're so excited about it," he says.

Already the team, at Washington University School of Medicine in St Louis, Missouri, has found one possible reason that people fail to build up resistance to repeated infections.

In mice at least, the branch of the immune system that remembers and fights specific pathogens is not enough to prevent a lethal virus infection. The team studied animals genetically engineered to lack particular immune molecules1.

"A mouse model is potentially a big breakthrough," says virologist Mary Estes of Baylor College of Medicine in Houston, Texas. But the mouse and human viruses are not identical, she warns; infected mice, for example, do not suffer gastrointestinal problems.

Ultimately, scientists hope to develop a vaccine against Norwalk-like virus for vulnerable hospital staff or the elderly. "Even travellers might want to take it," Estes says.

Cruise control

The explosion of outbreaks on cruise ships has continued into 2003 - despite the best efforts to scrub and disinfect them. So far, however, investigators are unclear whether there has been a genuine rise in the number of infections, or whether it is simply that more are being reported.

Despite its prevalence, the virus has proved almost impossible to study - because human strains cannot be grown in many lab animals or cells. Scientists have resorted to filtering the virus from diarrhoea - and feeding it to human volunteers.

Virgin stumbled on the mouse version when some of his mice started dying in their cages. The team identified the perpetrator by searching for viral genetic sequences amongst those of the mouse.