Nature Journal Club - Blog Posts

Eric D. Tytell

apetherick — 2008-12-23T17:13:39+00:00

University of Maryland, College Park

A neuroscientist marvels at our ability to learn unnatural tasks.

I find driving mind-boggling. As a neuroscientist studying motor control, I am amazed that nervous systems can adapt to the unnatural demands of operating a car. After all, humans did not evolve in habitats with steering wheels or accelerator pedals. What makes our ability to drive so curious is that it requires the modification of reflexes — twisting the steering wheel, for instance, rather than jumping aside, when an obstacle approaches.

Mark Wagner and Maurice Smith have shed some light on this curiosity. They show that the brain generalizes unnatural physical regimes, such as driving, to produce an appropriate corrective response to an unexpected change, even when that change has not been met before (M. J. Wagner and M. A. Smith J. Neurosci. 28, 10663–10673; 2008).

The duo trained undergraduates to reach quickly for a target with one hand while holding on to a motorized arm with the other. The faster the students reached, the stronger the motorized arm pushed them off course.

Initially, the students made large errors, but they soon compensated for the lateral forces. Were their brains learning the dynamics of the new force, though, or were they reassigning the activation of muscles in the spinal cord from those for reaching towards those that normally help to generate sideways pushes?

Surprising the students with a sudden pulse of force in the reaching direction provided an answer. They compensated with almost ideal corrective forces, which spinal reflexes alone could not have achieved. The slight delay in the students' responses also indicates that their brains were working from an internal model of the new force regime. How the brain develops such a model is unknown, but this paper should drive that research.

John Greally

apetherick — 2008-12-23T17:11:37+00:00

Albert Einstein College of Medicine, New York City

A biologist considers a link between jumping genes and immune-system enzymes.

Many viruses present a fierce threat to the body. They contain nucleic acids that, when free to roam in a cell's cytoplasm, elicit an immune response involving proteins called interferons. Pairings of the nucleic-acid residues cytosine and guanine are especially good at this, unless they carry a chemical modification in the form of a methyl group. This modification is the norm for 'jumping genes', or retrotransposons, which can move around the human genome and were probably once viral genes themselves.

A team led by Daniel Stetson at the University of Washington in Seattle has uncovered a useful twist to this tale. While searching for proteins that interact with cytoplasmic nucleic acids, the researchers came across Trex1. Mutated versions of Trex1 are known to cause chilblain lupus in humans, and in mice lead to autoimmune myocarditis, whereby the immune system attacks the heart. Stetson et al. say that mice lacking Trex1 have huge numbers of retrotransposons in their heart muscles.

Critically, the authors' molecular surveys reveal that Trex1 suppresses the rate at which jumping genes move around. This indicates that Trex1 protects the body from misidentifying its own parts as 'foreign' by degrading retrotransposons and thus preventing them from overloading the system (D. B. Stetson et al. Cell 134, 587–598; 2008).

That jumping genes have the potential to overwhelm the system in this way was unexpected. Most experts had assumed that the addition of methyl groups took care of quenching them. But if retrotransposons are made at a rate that triggers inflammation, as Stetson and his colleagues' experiments propose, it could open up a whole new avenue for research. Everyone studying lupus and related diseases should be excited.

William B. McKinnon

apetherick — 2008-12-23T17:09:39+00:00

Washington University, St Louis, Missouri

A planetary scientist has big hopes for a little world.

Right now, the most exciting object in the Solar System is Saturn's diminutive moon Enceladus. Its deformed south polar region emits copious amounts of heat along the length of several young, active ridges and fractures, as well as plumes of tiny ice particles, water vapour and other chemicals.

The Cassini spacecraft — equipped with plume-gas and particle analysers and clever imaging gadgetry — is currently in the neighbourhood. Seizing this opportunity, Gabriel Tobie of the University of Nantes in France and his colleagues have incorporated some of its recent measurements into theoretical models of tidal heat production on Enceladus (G. Tobie et al. Icarus 196, 642–652; 2008). Only the ebb and flow of tides could properly account for such prodigious geological activity on an icy moon that measures just 500 kilometres in diameter.

The authors start with the generally accepted idea that Enceladus has differentiated into a rock core and an icy mantle. They then show that the size of the tidal motion of the mantle is inadequate to generate the observed thermal emission, so there must be a fluid ocean sandwiched between the two solid layers. This is no great surprise, but Tobie et al. go further, showing that even if the mantle is made soft and deformable over the southern polar region (as the ice would be if it were relatively warm), a sandwiched, liquid ocean must reach at least as far as around the entire southern hemisphere.

The team imagines that, below Enceladus's south pole, tidal heating concentrates in warm, upwelling, convectively mobile ice. This, in turn, causes the cold, brittle surface layer to rupture — and the exposed warm ice sublimates, releasing trapped gases. It is a compelling picture, and one that promises to help unlock the internal activity of other icy satellites.

Jagadeesh Bayry

apetherick — 2008-12-23T17:06:27+00:00

INSERM, Paris

An immunologist applauds a protein that prunes intolerant white blood cells.

Spreading tolerance is a worthy cause. In the body, newly made white blood cells are rendered tolerant to the many thousands of native proteins. But, like any complex process, this one is not foolproof, and when it goes wrong intolerant white cells cause autoimmune disease.

One way that the tolerancespreading system can fail is by not having enough 'field agents' to pick off intolerant dissenters. Regulatory T lymphocytes (Treg), a type of white blood cell, are these field agents. They find and suppress other white cells that react to healthy parts of the body. Although it is known that people with low Treg levels tend to have autoimmune diseases, how the cells function has been unclear. Recently, however, researchers in Japan shed light on this mystery.

Kajsa Wing, now at the Karolinska Institute in Stockholm, and her colleagues focused on the protein CTLA-4, which is preferentially expressed by Treg cells and forms part of a rheumatoid arthritis drug called Abatacept. They bred mice without CTLA-4 on the surface of their Treg cells. The animals appeared healthy until maturity, then quickly developed autoimmunity. So CTLA-4 is needed for the field-agent system to operate, and merely expressing it in smaller quantities on other sorts of white blood cell isn't enough. Wing et al. then discovered that CTLA-4 on Treg cells interacts with and diminishes two proteins, CD80 and CD86, on the surface of dentritic cells, which show other white cells what to hunt (K. Wing et al. Science 322, 271–275; 2008).

All of this confirms that CTLA-4 should provide a means of treating autoimmune diseases. Blocking CTLA-4 should improve the capacity of dendritic cells to present dangerous native cells to the immune system. Clinical trials for cancer treatments that do just that are already under way. Now we have a clearer idea how they work.

Douglas Natelson

apetherick — 2008-12-23T16:27:06+00:00

Rice University, Houston, Texas

A physicist foresees a new era in electronics.

A material's electronic properties depend largely on its density of mobile charge carriers (electrons and holes). The most common way of tuning that density is 'doping'. This involves carefully adding atoms or molecules that donate or take up electrons from the surrounding material. But doping comes with a downside: these added impurities themselves become charged, so they scatter mobile charge carriers and muddy the predictability of the material's electronic properties.

How to avoid doping? Look to Julius Edgar Lilienfield. In 1925, he proposed what is now called the 'field effect', in which the material of interest functions as one electrode of a capacitor. When a voltage is applied to the other electrode, equal and opposite charge densities accumulate on the sample material. The density of charge carriers can be varied as it is in doping, but not to the same extent. Nonetheless, the field effect has an everyday role in transistors — which are the fundamental parts of consumer electronics.

Another of Lilienfield's inventions, the electrolytic capacitor, holds the key to much higher field-effect charge densities, which could have dramatic consequences. Researchers at Tohoku University in Sendai, Japan, recently used a polymer electrolyte to achieve sufficiently large charge densities at a strontium titanate surface to generate superconductivity (K. Ueno et al. Nature Mater. 7, 855–858; 2008). This has been seen before in doped strontium titanate, but the electrolytic capacitor approach avoids the disorder inherent in doping.

By using mobile ions in an electrolyte to attract charges in the sample, this quirky capacitor can build up charge densities approaching those of chemically doped electronic materials such as high-temperature superconductors. This opens up the possibility of transistor-like devices that can work with very low voltages.

Shanan Peters

apetherick — 2008-11-10T17:25:47+00:00

University of Wisconsin–Madison

A geologist questions a grand theory.

Atmospheric oxygen concentrations are falling. Breathing is difficult. Those that can't cope are collapsing and dying with symptoms akin to altitude sickness.

This may read like the first page of a Hollywood script, but, according to the oxygen-stress hypothesis, a similar scene occurred 251 million years ago at the end-Permian mass extinction, when up to 95% of all animal species died out. Like all good prevailing hypotheses, this one makes predictions that can be tested, if only the right rocks can be found.

Enter Tyler Beatty of the University of Calgary in Alberta, Canada, and his colleagues. They recently set up camp in the remote reaches of northwestern Canada, where rocks spanning the end-Permian extinction show a shift from Permian sandy carbonates to Triassic sand and mud. They found that fossils of entire creatures are not common at the boundary, preventing taxonomic analyses, but that fossils documenting sediment disturbance by animals are (T. W. Beatty et al. Geology 36, 771–774; 2008). This is fortuitous because such disturbance in marine sediments is linked to oxygen concentration. So these rocks may preserve a 'smoking gun' for an oxygen-stressed world.

However, the shallow marine sediments of the Early Triassic were pervasively burrowed by diverse organisms of the period, including large, oxygen-demanding arthropods. Only deeper-water sediments, deposited below wave-mixed surface waters, had the expected oxygen-stressed fossil traces.

This complicates the oxygen-stress story for the end-Permian mass extinction. Beatty et al. stop short of asking whether the end-Permian mass extinction was really caused by a massive reduction in atmospheric oxygen. But in light of their results, I am not holding my breath.

Bartosz Grzybowski

apetherick — 2008-11-10T17:20:42+00:00

Northwestern University, Evanston, Illinois

A physical chemist is pleased to learn that 'microscale' swimming isn't that hard after all.

Even if small organisms perfectly mimicked gold medallist Michael Phelps's technique, they wouldn't win a microswimming Olympics. The viscosity of water is so high that these little fellows have had to develop some unusual swimming styles. In 1977, E. M. Purcell formally expressed this idea with his famous 'scallop theorem'. He showed that swimming forwards cannot be achieved at the micrometre-scale with 'time-reversible' motions such as the back-and-forth wiggling of a rigid tail. Instead, tiny organisms must use complex, asymmetrical strokes.

But this is not always the case, according to engineers at the Massachusetts Institute of Technology in Cambridge and the University of California, San Diego. In July, they proved that time-reversible tail-wiggling or wing-flapping can be a viable mode of propulsion through a fluid, provided it is done next to a deformable interface such as a soft membrane (R. Trouilloud et al. Phys. Rev. Lett. 101, 048102; 2008). The reversible motions of the swimmer couple in a nonlinear way to the deformations of the interface, producing additional flows and forces that are sufficient for locomotion.

One of the most exciting extensions of this result might be in creating 'nanosubmarines' — a much-criticized dream of nanotechnologists to have devices navigate blood vessels, finding and fixing damaged organs as they go. The idea has so far seemed implausible because such machines would need elaborate nanopropellers — which are prohibitively difficult to build — to sculpt asymmetrical swimming motions. But what about using a simpler propulsion mechanism and relying on the deformations of blood-vessel walls to move nanosubmarines along? Is there a nanoshipyard out there somewhere to put this idea to the test?

Lynne B. McCusker

apetherick — 2008-11-10T17:17:33+00:00

Laboratory of Crystallography, ETH Zurich, Switzerland

A crystallographer celebrates a method with niche applications.

In 2004, Oszlányi and Sü introduced a new way to determine crystal structures from diffraction data. To many crystallographers, including myself, this was a remarkable development. Although most of us had assumed that the trend of incremental but significant improvements to existing methods would continue, we had not expected a completely different approach to be discovered. The algorithm is an elegant one, based on a very simple perturbation (called charge flipping) of electron-density maps that are generated during the structure solution process.

Initially, the algorithm was viewed as a curiosity. After all, existing methods for solving structures work very well about 95% of the time, so a new technique was not really needed. However, the algorithm caught the attention of some inquisitive crystallographers, who tested it on their favourite problem cases. The result is that, just 4 years after its development, the approach has found niches in areas in which traditional methods flounder (Acta Cryst. A64, 123–134; 2008).

Scientists studying aperiodic materials (modulated structures and quasicrystals, whose structures are best described in more than three dimensions) were among the first to recognize the possibilities offered by the algorithm, because it could be easily adapted to work in higher dimensions. Charge flipping has enjoyed great success with such structures, and is now considered the method of choice by this community.

The algorithm has also proved effective in solving the structures of polycrystalline materials, mainly because complementary information from other sources (such as chemical analysis and electron microscopy) can be easily included. Now small protein structures and neutron- and electron-diffraction data are being explored — no doubt further niches will be found.

Andrzej Pietrzykowski

apetherick — 2008-11-10T17:07:06+00:00

University of Massachusetts Medical School, Worcester

A molecular biologist considers the corollary of misbehaving ion channels

More than half a century ago, Hodgkin and Huxley hypothesized that pore-forming proteins found in a cell membrane could regulate the flow of ions across that membrane. These days, we classify ion channels according to the ions they allow through and the nature of the pore-forming protein. The crucial part of a pore is the protein's alpha subunit, which lines the pore. Auxiliary subunits, denoted by other letters of the Greek alphabet, merely tweak a channel's characteristics.

The basics infer an assumption: that different channels can interact with each other, but that subunits buried within a channel are 'married' to that channel 'for life'. A voltage-activated calcium channel can, for instance, form a pair with a large-conductance calcium-activated potassium channel. But a beta subunit of the calcium channel can associate only with the calcium channel's main alpha subunit, and a beta subunit of the potassium channel remains 'faithful' to the alpha subunit that surrounds the potassium pore.

However, assumptions should always be tested. In this case, Shengwei Zou and his colleagues at the University of Houston in Texas have taken the potassium channel in this example and shown that it is bound by an auxiliary beta-1 subunit of an L-type calcium channel (Cav1). When this subunit interacts with the potassium pore, it alters both the pore's kinetics and calcium sensitivity (S. Zou et al. Mol. Pharmacol. 73, 369–378; 2008).

I view this finding as part of an emerging theme, the ramifications of which could be profound. Ion channels may, in general, be much more dynamic structures than is currently recognized. This means that when researchers monitor a channel's activity they may not be recording exactly what they think they are — and that targeting ion channels with new drugs could produce unexpected side effects.

Ben Scheres

apetherick — 2008-10-14T12:20:28+00:00

Utrecht University, The Netherlands

A plant scientist finds beauty in floral arrangements.

On the face of it, flower arranging is a fiddly affair, and its underlying rules are not immediately obvious to the beholder. But a plant's flowers are always arranged in one of three basic architectures, or 'inflorescences'. These take the form of panicles, loosely but highly branched clusters in which each flower has its own stalk (as in the foxglove); racemes, in which flowers are arranged individually along an unbranched, growing stem (the snapdragon); or cymes, typified by a cluster of branches at the end of a stem that each terminate with flower (the forget-me-not). Simple rules must lie behind this, and simple rules are the foodstuff of mathematical models.

That is the logic behind the work of Przemyslaw Prusinkiewicz at the University of Calgary in Alberta, Canada, and his colleagues. Last year, they published a model in which they imagined that meristems grow into shoots or flowers according to the value of a factor that they named 'veg' (P. Prusinkiewicz et al. Science 316, 1452–1456; 2007). When veg is high, a shoot springs forth; when it is low, a blossom flourishes. Thus, if over time veg decreases at the same rate in all of a plant's growing tips, the model grows a panicle. Other simple rules give rise to a raceme or cyme.

Prusinkiewicz et al. found that, in Arabidopsis, a gene called LEAFY influences the value of veg. But how does this concept apply to plants with different architectures? Recently, Erik Souer of Vrije University in Amsterdam and his collaborators showed that modification of LEAFY activity is crucial for floral architecture in petunia, a cyme, just as the model predicts (E. Souer et al. Plant Cell 20, 2033–2048; 2008). They identify a protein that activates LEAFY only in developing flower buds and that is essential for their architecture. I find the tidy simplicity of these findings more beautiful than any bouquet.

Francisco Azuaje

apetherick — 2008-10-14T12:13:52+00:00

CRP-Santé, Luxembourg

A bioinformatician considers the general applicability of host-pathogen computer simulations

Computer simulations can help explain evolutionary phenomena such as co-evolution and the emergence of robustness. Unlike traditional methods of analysis, such simulations can incorporate detailed representations of environmental antagonisms — such as the pressure that parasites exert on the evolution of their hosts.

This is what Marcel Salathé of ETH Zurich in Switzerland and Orkun Soyer of the University of Trento, Italy, recently analysed at the molecular level. By using computer simulations based on mathematical models, they showed how robust signalling networks may evolve in parasite-infested cells (M. Salathé and O. S. Soyer Mol. Syst. Biol. 4, 202; 2008). In their simulations, signalling networks exhibited increasing redundancy in response to parasites, to the point that a node could be entirely removed without affecting network function. It seems that network redundancy may be a signature of parasitism present or past.

The paper is an exciting invitation to take a computational approach to evolutionary questions, by including more detailed mathematical representations. One could, for example, extend the host-parasite model to incorporate not just protein sequences, but also the ways in which genomic variation is generated, and see how everything plays out.

The approach could be generalized. National security studies, for example, might examine when and how attempts to infiltrate terrorist networks might actually make them more robust. And perhaps Salathé and Soyer's approach could be used to find ways of using environmental interference to reduce the robustness of disease networks, such as cancer signalling pathways, by examining their antagonistic interactions with therapeutic agents.

Nicola Hamilton & David Attwell

apetherick — 2008-10-14T12:12:03+00:00

University College London

Two neuroscientists are surprised by the link between a brain-chemical transporter and sexual orientation.

Many nerve cells in the brain release the chemical neurotransmitter glutamate to signal to other neurons via receptors. Dedicated transporters then remove glutamate from the extracellular space to end signalling.

Cystine–glutamate exchangers are unusual glutamate transporters because they do the reverse, adding glutamate to the extracellular space while removing cystine. David Featherstone of the University of Illinois, Chicago, and his colleagues have found that in the fruitfly Drosophila melanogaster, knocking down expression of a cystine–glutamate exchanger in non-neuronal glial cells leads to a dramatic change in the sexual behaviour of male flies: they mate with both males and females owing to altered processing of sex-specific chemosensory cues (Y. Grosjean et al. Nature Neurosci. 11, 54–61; 2008).

This behaviour may be caused by an increase in the number of glutamate signalling receptors, which is induced by the fall in extracellular glutamate concentration that follows transporter knockdown. Indeed, the effect of the knockdown could be reversed by feeding the flies a drug that reduces glutamate signalling, and could be mimicked by feeding normal flies a drug that enhances glutamate signalling.

These studies raise questions about whether human sexual orientation, long assumed to be due to a mix of genes and environment, could also be altered by perturbations of neurotransmitter signalling. Could differences in such signalling contribute to different sexual preferences?

The possibility of altering sexual preference pharmacologically is worrying. We cannot rule out a future regression to the twentieth-century idea that sexual behaviour should be regulated by society.

Michael K. Richardson

apetherick — 2008-10-14T12:06:34+00:00

Leiden University, the Netherlands

A developmental biologist highlights potential pitfalls of using stem cells that can 'remember' their origins.

For me, embryos are beautiful and their development is endlessly fascinating. They are experts at making new tissues, and accomplish this by using stem cells. Stem cells can develop into mature tissues such as bone or muscle; but, cleverly, some of their progeny remain in an undeveloped state, forming reserve supplies that remain in our bodies into adulthood.

Adult stem cells are found in tissues where cell populations are constantly being renewed, such as the testes, hair follicles and bones. We replace our entire skeleton every decade or so, and rely on stem cells in our bones to do this. Stem cells also have an important role in repair, swinging into action to deal with broken bones and other mishaps.

A recent study in mice yielded remarkable evidence that some of these adult stem cells remember where in the embryo they came from. Jill Helms and her colleagues at Stanford University in California grafted stem cells from one bone into another to see whether they would help repair fractures in the 'wrong' location. Stem cells transplanted from leg bones into fractured jaws failed to produce new bone (P. Leucht et al. Development 135, 2845–2854; 2008). Interestingly, the uncooperative stem cells continued to express a gene, Hoxa11, that acts as a kind of embryonic 'postcode' for the leg.

These findings have broad implications. They validate the concept of non-equivalence — that seemingly identical cells differ if they come from different places in the embryo — first enunciated by Julian Lewis and Lewis Wolpert in the 1970s, and show that it holds in the adult. More pragmatically, if some stem cells also have positional memory, doctors may need to make sure that they take stem cells from the right location to heal damaged tissues.

Caroline Harwood

apetherick — 2008-10-14T12:03:18+00:00

University of Washington, Seattle

A microbiologist hopes to disrupt bacterial 'decisions'

Cyclic-di-GMP is small but important. It is an intracellular signalling molecule that controls lifestyle choices in bacteria. When should a bacterium become virulent? When should it differentiate into a new cell type? When might it do better to stop moving around and stay still with many others? Bacteria that gather together tend to encase themselves and their neighbours in a carbohydrate slime, forming what is known as a biofilm. I, like many microbiologists, am keen to find ways to disrupt biofilms, and a better understanding of how cyclic-di-GMP works may provide a way to do this.

Recently, answers have started to emerge. First it was shown that cyclic-di-GMP can bind to certain proteins that modulate the activity of flagellar motors — which propel free-swimming bacteria — and to enzymes that make the biofilm-cementing slime. Then researchers found a protein that 'turns on' some of the slime genes when it attaches to cyclic-di-GMP. But one paper shows a completely new way in which cyclic-di-GMP can control bacterial lifestyle choices: by binding to a regulatory region, called a riboswitch, on a messenger RNA molecule (N. Sudarsan et al. Science 321, 411–413; 2008).

Ronald Breaker and his team at Yale University in New Haven, Connecticut, report how they used various molecular-biology techniques to demonstrate that part of the RNA hitches itself to cyclic-di-GMP. They also proved that cyclic-di-GMP-binding riboswitches from several bacterial strains can function as genetic 'off' as well as 'on' switches.

These findings are noteworthy because humans do not make cyclic-di-GMP, so the molecule could be a target for new antibiotics. Medicines that attack cyclic-di-GMP should be able to treat biofilm-related disorders such as periodontal disease and ear infections, which are often resistant to existing drugs.

John Harte

apetherick — 2008-08-29T20:15:23+00:00

University of California, Berkeley

An ecologist notes that important details are missing from climate-change models.

Unmitigated climate change will gravely reduce Earth's biodiversity. How much this will happen is calculated by combining data on how the species richness of different habitats varies with their area and projections of how much various habitat types will shrink as the planet warms.

But such grand analyses are blunt instruments; they miss numerous local processes. I have seen, for example, rosy finches and ptarmigans feeding on the contracting ring of vegetation that surrounds melting snow patches on Alpine slopes. Would these creatures survive the summer if the snow patches melted in late spring rather than late summer? Formed in existing mountainside hollows, snowbeds will not march uphill as the climate warms.

This question was recently answered by Robert Björk and Ulf Molau, then both at the University of Gothenburg in Sweden. They reviewed how the release of water and nutrients from the contracting edge of lingering snow patches sustains alpine life in midsummer by providing nourishing vegetation (R. Bjork and U. Molau Arctic Antarctic Alpine Res. 39, 34–43; 2007). The duo propose that bryophytes, grasses, sedges and rushes will be worst hit by the patches' earlier annual disappearance, and that these easy-to-graze species will be replaced by shrubs and trees, hitting Alpine herbivores hard.

This is just one example of the many impacts on biodiversity that fall through the cracks of current, coarse projections. Life and climate intersect on fine spatial and temporal scales — in the microclimates provided by terrestrial 'nurse plants' and in rock pools that form fleetingly in bedrock depressions. The disruption of these delicate intersections may add up to even more damage to biodiversity than the large-scale models predict. This deserves more study.