December 2006



How did the leopard get its spots? Recent research supports an idea first suggested by legendary code-breaker Alan Turing, says Philip Ball

‘After another long time, what with standing half in the shade and half out of it, and what with the slippery-slidy shadows of the trees falling on them, the Giraffe grew blotchy, and the Zebra grew stripy, and the Eland and the Koodoo grew darker, with little wavy grey lines on their backs like bark on a tree trunk …’
Rudyard Kipling, ‘Just so stories’, 1902

Kipling’s story of how the animals of Africa obtained their distinctive marking patterns is a fine example of Lamarckism – the inheritance of environmentally acquired characteristics. But the explanation that his contemporary biologists would have offered, invoking Darwinian adaptation driven by the markings’ ability to camouflage their hosts, was arguably little more than a ‘Just so story’ too.

Although it explained why a marking pattern would spread and persist in a population, it could say nothing about how such a pattern came to be, either in evolutionary terms or during the embryonic development of a particular zebra, giraffe or koodoo.

It cannot be down to genetic painting-by-numbers: the markings on two animals of the same species are recognisably alike, but not identical. So how do the melanin pigments of animal pelts get distributed across the embryonic epidermis in these characteristically blotchy ways?

Today’s favoured explanation is based on a mechanism proposed in 1952 by the British mathematician Alan Turing. He is best known for his work on artificial intelligence and his wartime code-cracking at Bletchley Park; but his paper on ‘The chemical basis of morphogenesis’1 was something else. It attempted to explain how a spherical ball of cells ends up as a shape in which different cells, tissues and appendages are assigned to different locations.

Turing proposed a set of differential equations which explained how that initial spherical symmetry could be broken. The equations describe a reaction-diffusion system, where some autocatalytic reaction can amplify random chemical inhomogeneities while the competing process of molecular diffusion tends to smooth them out. Turing’s calculations showed that patterning could emerge from this system.

In 1972, Hans Meinhardt and Alfred Gierer in Germany clarified the essential ingredients of Turing’s model. They showed that the chemical patterns are due to competition between an autocatalytic ‘activator’ molecule, and an inhibitor molecule that suppresses the activator.

If the inhibitor diffuses more rapidly than the activator, high concentrations of activator develop close to their source while being suppressed by the inhibitor over longer distances. This gives rise to isolated islands of activator, producing patterns of regularly sized and spaced spots and stripes.

But it wasn’t clear whether this system was anything more than a pretty mathematical fiction until 1990, when a team led by Patrick De Kepper at the University of Bordeaux, France, identified the first chemical Turing pattern, using a reaction that, when well mixed, oscillated between yellow and blue states. This was closely related to the Belousov–Zhabotinsky reaction, known since the 1960s to generate travelling chemical waves.

So are patterns in the living world really made this way? Theoretical activator-inhibitor systems have now been able to provide very convincing mimics of a wide range of animal markings, from the reticulated mesh of the giraffe’s pelt to the crescent-shaped rosettes of the leopard and jaguar, the spots of the ladybird and the stripes of the zebrafish. It all looks plausible enough, but the clinching proof – the identification of the diffusing chemicals responsible for pigmentation – has remained elusive.

Biomolecules called transforming growth factor b proteins seem to act as diffusing chemical morphogens of the sort Turing envisaged in fly and vertebrate embryogenesis, signalling the developmental fate of cells as they diffuse through the embryo. But there wasn’t any direct evidence of such morphogens acting as the agents of activator-inhibitor patterns, as they did in Turing’s original model.

Not, that is, until now. Thomas Schlake and colleagues at the Max Planck Institute of Immunobiology in Freiburg have finally discovered activator and inhibitor molecules at work in biological patterning.

They have found that the follicles of mouse hair are positioned in the epidermis by the protein products of two classes of gene, called WNT and DKK. The former appears to take the role of activator, inducing follicle formation, while several variants of DKK proteins act as inhibitors.2

Hair and feather positioning has long been suspected as an example of a Turing pattern – the equidistant, roughly hexagonally packed patterns are just what would be expected. Schlake and colleagues have made that case by looking at how over-expression of WNT and DKK alters the follicle patterns on mutant mice, showing that these match the predictions based on an activator-inhibitor model. It is probably the best reason yet to think that Turing’s intuition was sound.

Philip Ball is a science writer based in London, UK.

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It’s time to retrofit your kitchen pans with reflux condensers, says Dylan Stiles

In essence, organic chemistry is simply a matter of mixing two things together to make something new. Whether you’re simply neutralising acid with base, or executing some new-fangled domino cascade reaction, it’s really just putting things in a flask and cooking them up. So you might think that someone skilled in the art of chemical synthesis would also make a good chef.

Chemistry and cooking are, after all, two sides of the same coin, and perhaps it’s no surprise that we sometimes conflate the two. I’ve always thought that JOC (Journal of organic chemistry) could just as easily stand for the Joy of cooking.

Sadly, in my experience, it’s pretty rare to find a chemist who can produce anything even remotely edible in the kitchen. I’ve met researchers who can synthesise Taxol with one hand tied behind their back, yet are unable to prepare spaghetti.

Consider exhibit A: What’s cooking in chemistry: how leading chemists succeed in the kitchen. In this cookbook (reviewed in Chemistry World, June 2004, p63), top scientists from around the world were invited to submit recipes for their favourite dishes. It’s an amusing read but under no circumstances should you attempt to reproduce these procedures. Bob Grubbs makes a great olefin metathesis catalyst, but I don’t think his pecan pie is going to win any prizes.

My theory is that both chemists and chefs descended from a common ancestor, and that our phylogenetic tree split in two sometime during the glory days of alchemy. Since then our fields have evolved separately and are now so disparate as to bear only a passing resemblance.

There is some overlap, to be sure. A well-equipped synthetic lab will have a microwave apparatus (sans ‘popcorn’ setting), and a Cuisinart blender might well be distant cousin of a mechanical stirrer. And I have to concede that any process chemist would feel right at home in a brewery, with its giant reactors and distillation towers.

But too many chemists struggle in the kitchen. I attribute the majority of my own failures to a lack of standards with common cooking appliances. A recipe might say to sauté the halibut on ‘medium’ heat. Medium according to who? I sincerely doubt if the BIPM (International bureau of weights and measures) has a standardised ‘medium’ setting which manufacturers rigorously use to calibrate their stoves. I would be hung from the highest tree if I offered such vague instructions for the synthesis of one of my chemicals in the lab.

Worse still is the American cooking practice of measuring out solids by volume. The cup of brown sugar that you put into Grubbs’ pecan pie could vary by ± 20 per cent depending on how densely you pack it. In this respect European cooking technology is light years ahead of ours. On this side of the pond I can only dream of the day when balances are commonplace in the kitchen and recipes specify quantities by mass.

I have ideas for a few simple changes in the kitchen that would greatly improve chemists’ performance. Standardised joint sizes on pots and pans would not only make all cookware interchangeable, but also allow you to incorporate elements like addition funnels and reflux condensers into your cuisine. Consider this low-tech saucepan modification.

Dylan Stiles

Dylan Stiles

Normally, when a protocol calls for something to simmer, you put a lid on the pan, turn the heat down to low, and rely on air cooling to keep the vapours contained in the pot. This arrangement is woefully inefficient, and volatiles are bound to escape. But if you simply place a bag of ice on top of the lid, you have something akin to a coldfinger, locking in the flavours and making for some tasty vittles.

I tried this experiment with two side-by-side batches of experimental chicken curry, feeding the product to my roommates in a double-blind study. Preliminary results indicate enhanced delectability with the modified apparatus. Another triumph for kitchen chemistry.

Dylan Stiles is a PhD student based in California, US.

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Derek Lowe looks at the recent failure of Pfizer’s cholesterol drug, torcetrapib, and asks what it means for the future of pharmaceutical research

The biggest story in the drug industry for 2006 took until December to announce itself, and many people immediately wished they’d never heard of it. Pfizer’s massive clinical failure with torcetrapib was more than enough of a catastrophe for everyone.

The drug, which saw its first clinical tests in 1999, appeared to sail through subsequent trials which proved torcetrapib could boost the amount of ‘good’ cholesterol, or high-density lipoprotein (HDL), in patients.

But on 2 December, Pfizer announced that the latter stages of Phase III trails had shown an increased risk of mortality and cardiovascular events in people taking the drug, and immediately stopped all clinical trials.

The drug works by inhibiting cholesteryl ester transfer protein (CETP), which regulates the exchange of cholesterol and triglycerides between plasma lipoproteins. Less CETP activity essentially means more HDL, which helps to reduce the build up of fatty atherosclerotic plaques that block blood vessels. This mechanism nicely complements drugs that reduce the body’s levels of low-density lipoprotein, such as Pfizer’s own blockbuster statin, Lipitor.

Inhibiting CETP has been a target for drug development teams for many years now. A number of companies have had compounds in this area, but many have fallen by the wayside, often for reasons that haven’t been made clear. One difficulty has surely been the nature of the protein itself. Built for binding lipids, most of the compounds that can alter its function have to be large and greasy themselves, and that never helps a drug’s chances. Those properties mark a compound as a foreign interloper, and affect everything from the time the compound reaches the gut to the rate it’s cleared from the bloodstream.

People are spending hundreds of millions of dollars to find out more about CETP. Roche (with their partners at Japan Tobacco) and Merck are known to be in the clinic with CETP inhibitors of their own. It must not have been a fun weekend around their clinical departments when the Pfizer news broke. If torcetrapib’s failure had immediately doomed the competing compounds, at least the pain would have been over with in one shot. But all the competing companies are going to have to live in a thick atmosphere of fear and hope for some time, because – as could be carved in stone over the doors of clinical research departments everywhere – it isn’t that simple.

For one thing, it’s not clear whether torcetrapib failed because of its CETP activity, or just because it there was something odd about torcetrapib itself. And there’s an added complication – the trouble only showed up in the patients that were also getting Lipitor, which means that drug–drug (or mechanism–mechanism) interactions can’t be ruled out yet.

What really obscures things is that Roche’s compound seems to act on CETP through a different mechanism, and thus probably through a different binding site. We’re going to know a lot more about HDL and cholesterol trafficking by the time all this is over, and we’ll certainly have paid to find out.

There’s a lot of money riding on such mysteries, and yet no one has the slightest idea how everything will play out. It’s this ‘place-your-bets’ atmosphere that drives upper management insane all across the business. Compared to some industries, it’s like making a living by staggering blindly around in a casino, waving a wad of cash in one hand and a fistful of test tubes in the other. It’s tempting to think that modern management techniques, better scientists, or more software must surely make this stuff manageable, but nothing has worked so far.

Just ask Pfizer. The largest drug company in the world just lost what could have been their biggest-selling drug ever, and only time will tell whether the clinical disaster was avoidable. But for now, everyone in the field is holding their breath, because nothing’s obvious and nothing’s for certain. You could carve that in stone, too.

Derek Lowe is an experienced medicinal chemist in the pharmaceutical industry, working on preclinical drug discovery.

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Different types of rat respond to drugs in substantially different ways that can be tracked by metabolic analysis, according to scientists who say their finding has major implications for designing animal experiments…

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David Leigh, professor of organic chemistry at the University of Edinburgh, UK, likes to liven up his lectures with a few magic tricks, as he explains to Alison Stoddart.

And for some magical research, how about the whirlpool-patterned tin templates that Chinese researchers have used to grow beautiful disks and wires of silicon; or the finding that hydrogen fuel cells might not need expensive platinum catalysts, but can be powered by enzymes?

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Star-nosed moles and water shrews can smell underwater by blowing out a continuous stream of bubbles, report US researchers.

The news overturns received wisdom that underwater olfaction is impossible – because a sense of smell relies on the ability to sniff air – and raises the possibility that subaquatic odour detection might be a widespread skill.     

 

 

 

 

       

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US researchers have developed a molecule they hope could provide an early warning system for Alzheimer’s disease.

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The sorts of microbes living in your gut could determine how fat you are, report US researchers. But it’s not clear whether this finding could lead to new therapeutic treatments for obesity. The chemistry of obesity is also explained in one of Chemistry World‘s December 2006 features.

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With the publication of the European Commission’s first calls for proposals for FP7 working programmes imminent, the European Technology Platform for Sustainable Chemistry (SusChem) is organising a Brokerage Event on 24 January. The event at the Le Meridien hotel, Brussels will provide information on opportunities for SusChem- relevant topics in the first FP7 calls and give a forum for networking between potential partners to kick-start consortia building. As closing dates for the first proposal submissions are expected to be as soon as March 2007, researchers in Europe have to build or consolidate consortia to respond to the calls quickly. The brokerage event is designed to support the process of consortia building and will be of interest to industrial and academic researchers who are active in process technologies, materials nanotechnology and industrial biotechnology. Participants are invited to present their expertise or project ideas with a poster in order to actively seek collaboration partners. SusChem is also working on a user-friendly database for use by potential partners for SusChem and related collaborative projects. This SusChem Partnering Facility will facilitate the formation of new collaborative projects by providing an ‘advertising’ space to recruit team members to fill skill gaps or allow individual researchers and teams to promote their field of expertise or a new relevant project idea. For detailed information on the event including an agenda and registration form, please visit the SusChem website

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At this time of year there are reminders everywhere of the beautiful structures that water can form when it freezes. But the ice crystals predicted in computer simulations by Xiao Cheng Zeng and colleagues at the University of Nebraska, Lincoln, US, are as striking as any snowflake …

NanoIce

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