Stripping Down Science (13 page)

Ask anyone who made the world's best violins and they'll inevitably answer ‘Stradivari'. But science is beginning to undermine the reputation of this great instrument maker who, it seems, might owe at least part of his success to an attempt at chemical pest control, rather than just his craftsmanship.

Antonio Stradivari was born in 1644 and lived in Cremona, a city in north-west Italy. He set himself up as an instrument maker in the 1680s but his ‘golden period', during which he is believed to have produced some of his best instruments, didn't come until the 1700s, by which time he was over 70 years old. About 600 of his instruments are thought to survive today and, in good condition, they are each worth at least US$5 million. The hefty price tag reflects the fact that not only are they 300 years old, they're thought to be genuinely unrivalled in terms of the quality and purity of the sound they produce. Effectively they're the Rolls-Royce Silver Ghosts of the musical world.

Not surprisingly, very few owners are willing to donate their instruments ‘in the name of science' to help researchers find out why they are so special. But it's been a lifetime ambition of Hungarian-born scientist, musician and violin maker Joseph Nagyvary, who's also an emeritus professor of biochemistry at Texas A&M University,
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to do just that. Now, thanks to some tiny wood fragments donated by restorers working on these violins, he thinks he knows the answer.

Nagyvary used a technique called infrared spectroscopy to dissect the chemical structure of the wood in the fragments. He then compared it with similar samples collected from an old English and an old French instrument dating from the same period. The results were striking. The trace from the Stradivarius was very different from the other European instruments. It showed signs of having been chemically brutalised. The amount of lignin in the wood was reduced, and the hemi-cellulose, which acts like a molecular bridge holding the wood together, was greatly damaged. This would dramatically alter the
resonant properties of the wood and change its acoustics, accounting for the distinctive sound said to single out these instruments.

But what could have caused this degradation in the wood? In an attempt to reproduce the effect, Nagyvary tried boiling and even baking samples of modern wood, but the treatment wasn't harsh enough. Instead, it seems Stradivari, or the carpenter who supplied him, must have resorted to chemical means, probably in the form of copper and iron salts, which are strongly oxidising and could conceivably have damaged the wood in this way. To find out exactly what chemicals they must have used will require access to more wood fragments, which could take some time. ‘These samples are hard to get,' Nagyvary says. ‘You cannot approach Itzhak Perlman and ask him to give you a chunk of his Stradivarius for analysis.'

But why chemically massacre your future instrument anyway? Nagyvary thinks the answer is all down to a primitive attempt at preservation. ‘I am a heretic in this regard. I really don't think that Stradivari did this for acoustical purposes. I think that was a rather routine process around that time, in Cremona, where most woodworkers
had to preserve their wood against the woodworm. Stradivari was a marvellous craftsman,' Nagyvary observes, ‘but the magnificent sound of his instruments is a lucky accident.'

You're having me on! I hear you exclaim. But no, mad as this might sound, it's no myth. With the magic of modern science it's possible to give a laboratory fruit fly the smelling ability of a mosquito, which is exactly what a group of scientists did recently to work out how these bloodthirsty winged menaces hunt us down for dinner.

Mosquitoes are universally acknowledged as the most dangerous animals on earth owing to the number of deaths they cause by spreading diseases like malaria, dengue and yellow fever, which together run to hundreds of millions of cases per year. Scientists and doctors are therefore very eager to track down how it is that mosquitoes
home in on us, and what attracts them to humans in the first place, because if we can understand how they're doing this then we can come up with better repellents. At the moment, substances like DEET (diethyl toluamide) are produced by chemical trial and error, but by knowing exactly how a mosquito identifies its next meal, it ought to be possible to produce more macho molecules tailor-made to turn a hungry mosquito into an anorexic.

Fundamental to the mosquito's human-tracking ability is its olfactory arsenal. The antennae that project from its head are covered in receptor molecules, which resemble miniature chemical docking stations that are each wired up to an individual nerve that connects to the animal's brain. Different types of receptors are specialised for picking up different types of odour molecules, which tend to have specific chemical shapes or structures. So when one of these odour chemicals bumps into a receptor that is the right shape to recognise it, the receptor is activated and fires off impulses down the adjacent nerve, signalling a ‘hit'. The brain then adds together all of the incoming information to build up a picture of what the world smells like and from which
direction certain odours are arriving.

This sounds simple enough but, by studying the mosquito genome, scientists have found the genetic recipes for more than 70 of these different receptors. They've also found that many odour chemicals can activate more than one type of receptor at once, which makes it very difficult to understand exactly which odours are detected by which receptors and therefore how to make an insect repellent to best block them.

Now enter Yale researcher Allison Carey.
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Using a family of mutant fruit flies in which one of the groups of nerves in their antennae are devoid of odorant receptors, she added to these anosmic neurons, one at a time, the genes for 72 different mosquito odorant receptors. This was the molecular equivalent of stitching a dog's nose onto a human, because it bestowed on the resulting flies the ability to smell whatever chemicals each of the individual genes normally enable mosquitoes to detect. By recording the electrical activity from the individual nerves inside the fruit fly antennae as the insects were exposed to 100 different chemicals and odours in turn, including substances known to be produced by
humans and the bacteria that live on human skin, it was possible to work out what contribution each gene makes to the smell-detecting repertoire of a mosquito.

This means that researchers now know which classes of chemicals mosquitoes can respond to and which ones are likely to be key targets in developing novel repellents. For instance, 27 of the receptors studied responded particularly strongly to compounds found in human sweat. Now they've been identified, research is focusing heavily on how these receptors work, how they interact with the odour molecules they detect and how best to block them or, paradoxically, activate them.

‘We're screening for compounds that interact with these receptors,' says John Carlson, one of the other scientists involved in the study. ‘Compounds that jam these receptors could impair the ability of mosquitoes to find us. Compounds that excite these receptors could help to lure mosquitoes into traps or repel them. The best lures or repellents may be cocktails of multiple compounds. The world desperately needs new ways of controlling these mosquitoes, ways that are effective, inexpensive, and environmentally friendly.'

FACT BOX

Turning mosquitoes into flying vaccinators

Nuisances as mosquitoes are, and desperate as scientists are to disable them, researchers have nonetheless also been sizing them up as mobile hypodermics capable of delivering a flying vaccination service. The work is based on the premise that, every time they take a blood meal, female mosquitoes first inject their saliva, containing anticoagulants and immune-evading agents, around the blood vessel puncture site. This is what provokes the itchy inflammatory aftermath but is also responsible for transmitting infectious agents like malaria, which the mosquito regurgitates into the wound when it feeds.

Shigeto Yoshida, from Jichi Medical University in Japan,
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reasoned that it ought to be possible to exploit this unpleasant aspect of the insect's behaviour in a beneficial way.
He set about genetically modifying
Anopheles
mosquitoes to make them produce in their saliva a protein called SP-15, which is critical for the spread of another major disease-causing parasite called
Leishmania
. Mice bitten repeatedly by these modified mosquitoes developed antibodies to SP-15, which other researchers have shown can protect against
Leishmania
transmission. ‘Following bites, protective immune responses are induced, just like conventional vaccination but with no pain and no cost,' says Yoshida. ‘What's more, continuous exposure to bites will maintain high levels of protective immunity, through natural boosting, for a lifetime.'

The next step will be to test whether mice vaccinated by these mosquitoes really can be protected from
Leishmania
infection in future. The odds are that it should work, because the same SP-15 protein has been successfully tested as an experimental vaccine previously. But whether this flying vaccinator technology will take off in general and for other types of vaccines is another matter. Some may feel
slightly stung by the idea of a natural and uncontrolled vaccination system delivering unmetered drug dosages and boosters indiscriminately.

This sentiment is pre-empted by Yoshida himself in his paper describing the work in the journal
Insect Molecular Biology
: ‘The concept of a “flying vaccinator” transgenic mosquito is not likely to be a practicable method of disease control, because “flying vaccinator” is an unacceptable way to deliver vaccine without issues of dosage and informed consent against current vaccine programs. These difficulties are more complicated by the issues of public acceptance to release of transgenic mosquitoes.'

Still, it might be one to have in the bag for when times get really tough!

FACT BOX

Malaria in children: a case of mistaken identity

Mosquitoes are directly responsible for causing over 500 million cases of malaria per year, the annual death toll from which is over one million, mostly young babies and children aged between six months and three years in sub-Saharan Africa. Why does this disease hit this age group much harder than any other? The answer, it turns out, is a case of mistaking friend and foe.

Christopher King, a researcher from Case Western Reserve University in the US,
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followed up 586 babies born in Kenya from the time they were born until the age of three. He collected umbilical cord blood samples from the babies and also took a specimen of blood from each of the babies' mothers. Tests showed that some of the mothers were infected with malaria at the time when they
gave birth, suggesting that the baby might also have been exposed to malarial antigens – chemical markers made by the parasite – which would have been circulating in the mother's bloodstream.