University of California, San Francisco

A computational biologist looks at how mRNA length changes during development.

I am always amazed by how we start as a fertilized egg and develop into a complex, multicellular organism. This feat occurs despite the fact that the DNA in every cell — even the most specialized ones — remains, for the most part, unchanged.

One method of regulating gene activity in differentiated, or specialized, cells is through the messenger RNA (mRNA), the code of which is translated to make proteins. For example, proteins and other RNAs can bind to the untranslated regions (UTRs) at the 5' and 3' ends of mRNAs to regulate mRNA stability and translation.

The constitution of the 3' UTR itself can be regulated through alternative polyadenylation, whereby one of several possible UTR sites is cleaved, followed by the addition of adenosine-based molecules to its end. A broad shift in cleavage site choice — and thus 3' UTR length — during mammalian development was recently described by Bin Tian and his team at the University of Medicine and Dentistry of New Jersey in Newark (Z. Ji et al. Proc. Natl Acad. Sci. USA 106, 7028–7033; 2009).

By analysing genomic data, they show that 3' UTRs generally get longer during development and cell differentiation. The authors further show that most of the genes in which 3' UTRs are lengthened are also those that are increasingly suppressed during differentiation, such as the genes for DNA replication and cell division.

These findings bring to the forefront an underappreciated mechanism of genetic regulation that is likely to be important for normal cell differentiation. It is fascinating how many steps of the central dogma (DNA to RNA to protein) are controlled. This seems to be how evolution has managed to take a relatively simple cell and multiply it to form the complex body plan of the human.

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Medical Research Council, Cambridge, UK

A biologist looks at the effect of a dynamic nuclear environment on gene expression.

In many organisms, including animals, genes are arranged linearly on chromosomes. But this linear order is largely meaningless during transcription, when RNA is made from DNA. Instead, a very different three-dimensional arrangement of genomic regions emerges in which structural flexibility and ability to reorganize become crucial to gene expression. Some regions loop out dynamically, moving far from their neighbours. Genes can participate in 'transcription hotspots' in close association with genes from other chromosomes. But the question remains as to what leads this dance. Is the chromosomal reorganization a cause or a consequence of transcription?

Using Hox clusters — groups of genes important in development — Wendy Bickmore of the Medical Research Council in Cambridge and her colleagues start to answer this question. Hoxb and Hoxd have very different environments in terms of their location on the chromosome and expression of their neighboring genes. The authors found that during tissue differentiation, Hox genes loop out and undergo active transcription. This reorganization then spreads from the Hox locus into adjacent genomic regions, but does not necessarily affect transcription of neighbouring genes (C. Morey Genome Res. doi:10.1101/gr.089045.108; 2009).

The authors propose that on activation, structural changes alter the constraints on genes' expression, allowing them to loop out and explore a much larger transcriptional environment within the nucleus. The team concludes that positioning outside of a chromosomal region is important for, but not a driver of, transcriptional activation.

These findings have broad implications: first, dynamic reorganization of chromosome territories is necessary but not sufficient for activation. Second, this reorganization is associated with modification to DNA's structural packaging, which can permanently alter a cell's nature.

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University of California, Davis

A cell biologist looks at the risk and promise of a new insight into stem cells and cancer.

I study both stem and tumour cells, and am fascinated by their close relationship. Both exhibit pluripotency — the capacity to develop into any cell type — and the ability to cause cancer. Even some apparently normal stem cells can cause tumours, whereas others, sometimes from the same culture, lack this power. It seems that not all stem cells are created equal — even in the same dish.

A recent paper from Mickie Bhatia's group (T. E. Werbowetski-Ogilvie et al. Nature Biotechnol. 27, 91–97; 2009) is the first to directly address this heterogeneity in human embryonic stem cell (ESC) cultures. The team found that individual human ESC lines contain significant subpopulations that vary in a number of ways, including in tumorigenicity.

Variant human ESC lines were about 20 times more tumorigenic than the cultures they had been derived from and showed small changes in chromosome structure. These could be identified by array-based comparative genomic hybridization (aCGH), but were not detectable by standard karyotyping. Thus for 'normal' stem cells being considered for use in regenerative medicine, karyotyping is not enough. Screening should also include aCGH, and perhaps an analysis of gene-expression patterns.

This previously covert diversity has implications for both tumour biology and medical applications involving stem cells. It may shed light on the 'locked in' self-renewal that is emerging as an important feature of many sorts of tumour and tumour stem cell.

The heterogeneity of human ESC cultures represents an additional hurdle in terms of producing safe stem-cell-based transplants. At the same time, it may offer a valuable bonus: the chance to purify variant human ESC sub-lines that are less tumorigenic.

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MRC Laboratory of Molecular Biology, Cambridge

A molecular biologist gets excited about making designer proteins in cells.

The genetic code describes the relationship between the heritable information in the genome and the amino acids that are strung together to make proteins. This code, like any that contains redundancy, is open to hacking, and I have long been fascinated by how the process of translation, by which cells string amino acids together, might be reprogrammed to make new polymers. Several labs have already manipulated cells to incorporate designer amino acids into their proteins.

But Peter Schultz and his colleagues at the Scripps Research Institute in La Jolla, California, have achieved something remarkable. Proteins are made from a set of 20 amino acids, each of which contains an amine and a carboxylic acid group flanking a central carbon atom. Schultz's team engineered a bacterial cell to work with amino-acid-like molecules called -hydroxy acids that have an alcohol group where the amine would normally be. During translation, instead of forming an amide bond to link polymer subunits, this -hydroxy acid forms an ester bond (J. Guo et al. Angew. Chem. 120, 734–737; 2008).

Replacing a nitrogen and a hydrogen atom in a polymer chain with an oxygen atom might seem like a slight change, but it means that a protein can now be specifically cut at the ester bond in basic solution. Making esters from -hydroxy acids may first have been achieved with ribosomes in a test tube in the 1970s, but turning the process into a heritable, genetic property is a major advance: it takes synthetic biologists closer to creating organisms with designer codes to make new polymers.

One day soon, the creativity and skill with which chemists can make molecules will be coupled to the selective power of organismal evolution. And we will watch new life forms boot up.

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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.

Posted by Anna Petherick at 05:07 PM | Permalink | Comments (0) | TrackBacks (0)

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.

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Semmelweis University, Budapest, Hungary

A network scientist highlights active sites of enzymes, cells, brains and society.

For proteins, chemical binding is a tricky business. Special signals must be sent across a sea of water molecules to the desired partner, and complex mutual structural adjustments (a fluctuation fit) must be completed before each successful binding event.

I have long taught that a protein at its lowest-energy conformation still has regions of higher energy. But I've always been intrigued: how is the extra energy of the active sites preserved? And why do we need such big enzymes when their active sites occupy only a tiny region?

Piazza and Sanejouand found part of the answer by identifying special energy-preserving segments of proteins (F. Piazza and Y.-H. Sanejouand Phys. Biol. 5, 026001; 2008). Taking into account the effect of the surrounding water, they modelled proteins with a computer program that arranges oscillating elements in the same pattern as amino acids in real proteins. In most of these proteins, they identified a few easily excitable segments that collected and harboured long-lived, localized vibrations. An analysis of 833 enzymes showed that these segments co-occur with the catalytic active sites; are located on the stiffest parts of the proteins; and have many connections but are surrounded by a less well-connected environment.

The generality of many network properties prompts me to ask: can we find 'active sites' of cells, brains, ecosystems and societies? Piazza and Sanejouand's segments correspond to Ronald Burt's "structural holes" in social networks — whereby areas of greatest economic potential are areas of low connectedness, where brokers can make new connections. Indeed, not only amino acids, but people may also act as brokers, mediators and catalysts. It may be worthwhile to think about creative, broker proteins as drug targets. One could even imagine creative sets of neurons.

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Institute for Cell Biology, University of Munich, Germany

Unexpected links between cellular organelles continue to unfold.

As a graduate student, I was intrigued by centrioles. Their beautiful ninefold symmetry, occurrence in pairs and positioning at the heart of the cell —as a constituent of the microtubule-organizing centrosome — made them appear significant. But how they are built and replicated, and even their true purpose in cell division, remained enigmatic.

Adding to my fascination was the fact that, in my cultured cells, one of the centrioles often acted as an anchor, or basal body, for a cilium-like appendage — even though the endothelial cells I used were not thought to ever have cilia.

Once considered a biological oddity, these stubby, non-motile 'primary' cilia are now known to be present in most cells of the human body (see here) and probably serve as essential sensors whose disturbance is linked to a growing list of diseases.

I have always wondered whether there is an additional functional link between centrioles and primary cilia. A recent paper (A. Robert et al. J. Cell Sci. 120, 628–637; 2007) shows that a protein involved in the biogenesis of primary cilia is also a bona fide constituent of the centrosome. Moreover, this centrosomal/ciliary component is tied into the regulation of the cell cycle.

This finding joins a series of recent discoveries of proteins that are both centrosomal and ciliary. Taken together, these studies are revealing a truly novel functional link: centrioles are there to make primary cilia; primary cilia act as sensors of external stimuli; and, as other studies have shown, external stimuli can regulate cell proliferation. So the mysterious organelles of my graduate student days are being demystified, but the story that unfolds turns out to be even more fascinating than I expected.

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University of Chicago, Illinois, USA

An evolutionary geneticist is surprised by genes of unknown origin.

I once thought that, like us, every gene must have a mother. But recent work has identified some genes that seem to have no genetic ancestry. These 'motherless' genes pose a new challenge to understanding the molecular mechanisms and evolutionary forces that shape our DNA. This isn't the first time we've had to revise our ideas about gene evolution.

About 40 years ago, geneticist Susumu Ohno proposed that new genes originate when an existing gene duplicates, then one of the copies evolves a new function. Working with Chuck Langley in the early 1990s, I had the luck to discover a gene in flies that added another strand to Ohno's story. The gene, named Jingwei, is a chimaera that formed through the combination of two existing genes.

Since then, researchers have identified many other 'new' genes assembled from unrelated genes and mobile DNA elements. Often the sequences' origins can be identified. When they can't, researchers have simply assumed that subsequent evolution has masked the relationship of the gene to its ancestral sequences.

But this is unlikely to be the case for hydra, a gene found recently in Drosophila melanogaster and closely related species (S.-T. Chen et al. PLoS Genet. 3, e107; 2007). No homologous sequences are found in a species that diverged from those carrying hydra only 13 million years ago — too recently for mutations to have obscured any related sequences. This implies that hydra arose de novo.

Another group has found a further 16 de novo genes in flies, which they propose evolved from non-coding DNA (D. J. Begun et al. Genetics 176, 1131–1137; 2007 and M. T. Levine et al. Proc. Natl Acad. Sci. USA 103, 9935–9939; 2006). These genes beg further study: what initiated their formation?

Editor's Note, the entry previously misspelled the name of the author's institution. Nature regrets the error.

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Collegium Budapest, Hungary, and The Parmenides Foundation for the Study of Thinking, Munich, Germany

A theoretical biologist recommends thought-provoking reading on the origin of translation and the genetic code.

As Francis Crick and his co-workers once noted, "the origin of protein synthesis is a notoriously difficult problem". Our best hopes of resolving this problem begin, in my opinion, in an RNA world.

The RNA-world hypothesis holds that RNA emerged before DNA and proteins, neatly separating the origin of life from that of the genetic code and its translation. The question then becomes: how did RNA evolve to make proteins?

In a recent paper, Yuri Wolf and Eugene Koonin of the National Institutes of Health in Bethesda, Maryland, present one scenario (Biol. Direct 2, 14; 2007).

They rightly call attention to studies that suggest that protein-based aminoacyl-tRNA synthetases, which are involved in the first steps of assembling amino acids into proteins, are relatively late evolutionary inventions. This forces us to accept the idea that protein synthesis is older than such synthetases.

Before the evolution of synthetases, the only agents that could conceivably have marshalled amino acids are RNA enzymes, or ribozymes. Wolf and Koonin share my view that the recruitment of amino acids was driven by selection for enhanced catalytic activity, and that the ancestor of the large ribosomal RNA that catalyses protein synthesis in today's cells — a molecular 'fossil' — was a catalyst that linked only two amino acids.

I am less happy with these authors' suggestion of a relatively late switch from peptide-specific proto-ribosomes to those that could use an external template such as mRNA to synthesize peptides with arbitrary sequence — but they may well be right.

They lay out an evolutionary sequence that is more complete than the scenario I once proposed. I highly recommend this well-written, thought-provoking paper.

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Massachusetts Institute of Technology, Cambridge, USA

A biological engineer searches for simplicity.

Several years ago, a good colleague suggested that I read about a discussion held in 1864 on nuts and bolts (J. Franklin Inst. 77, 344–351; 1864). The focus was a paper by one William Sellers that argued for the adoption of a uniform system of screw threads — 60° angles, squared off along the edges.

Machinists across the United States eventually started producing nuts and bolts according to Sellers' scheme. As a result, hardware stores now offer a wide selection of standardized parts that can be used in combination and behave as expected.

Inspired by this example and others, I have been studying how synthetic biological parts might be made as regular and easy to use as Sellers' nuts and bolts.

The starting complexity of nature has led some distinguished researchers to doubt such work is practical. But given that there has been little research on manufactured bio-simplicity, this seems premature.

And there are examples: a team at the California Institute of Technology in Pasadena recently developed a uniform system for engineering simple biological switches made from ribonucleic acids (M. N. Win and C. D. Smolke Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0703961104; 2007).

The 'nuts and bolts' of the switches are RNA sensor and actuator domains. The method for combining any sensor domain to an actuator domain through a third communication domain provides the 'uniform screw threads'. Because such switches are produced by a standard process, many switches could be quickly programmed to control diverse cellular functions in response to myriad molecular inputs, from small molecules, to peptides, to nucleic acids.

I suspect that further efforts to engineer biological simplicity will have similarly powerful results.

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University of California, Berkeley, USA

A biochemist marvels at a molecule that shares his love of playing with fire.

I like to capture my students' attention by recounting how my early fascination with fire inspired my interest in the stability of sugars.

Glucose will 'burn' to carbon dioxide and water, liberating lots of energy. But it is stable enough that you can stamp on it without triggering the reaction — the energy barrier to the reaction is too high.

In my research, I am interested in how biology harnesses and controls oxygen reactivity. Most reactions, such as burning glucose, are held back by an energy barrier to getting things started. Enzymes can bypass this, finding a lower energy route through some reaction intermediate, to carry out a 'controlled burn'. Their control is not perfect, sometimes causing damage to both themselves and surrounding molecules, but by and large it works.

Typically, these enzymes have metal or organic components, which drive the oxidation. I often tell students that enzymes need their metal and organic cofactors because the 20 naturally occurring amino acids cannot carry out all the chemistry. Two recent papers shake that belief.

The surprise comes from the enzyme DpgC, which is involved in the biosynthesis of the antibiotic vancomycin. The first paper (C. C. Tseng et al. Chem. Biol. 11, 1195–1203; 2004) reports that DpgC uses oxygen in a complex dioxygenase reaction with no bound metal or organic cofactor.

More recently, researchers reported the structure of DpgC and confirmed that it has no cofactor (P. F. Widboom et al. Nature 447, 342–345; 2007). They find that the enzyme has a structure known as an oxyanion hole, which helps to stabilize the reaction intermediate.

I am still amazed that DpgC does oxygen chemistry with no help — and my students should be too.

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University of California, San Francisco, USA

A cancer geneticist delves into family matters.

A mystery lies at the heart of a small family of growth signalling enzymes (K-Ras, H-Ras and N-Ras), which are widely mutated in human cancers. In culture, all three enzymes have similar functions, but different ras genes are associated with cancers in different tissues.

My laboratory, for instance, noted more than 25 years ago that skin cancers show activation of H-ras. Others have demonstrated that lung, colon and pancreatic cancers show activation of K-ras, whereas N-ras is the oncogene of choice in melanomas and some leukaemias.

What determines this intriguing specificity? Are the enzymes' functions somehow modified in certain tissues in vivo? Or is it regulation of the genes, affecting where and when they are expressed, that matters?

We may get some answers by following the lead of an elegant study (N. Potenza et al. EMBO Rep. 6, 432–437; 2005). In this work, the authors knocked out K-ras in mice, but simultaneously replaced the gene with its close relative H-ras, doctored to have the regulatory elements of K-ras. Mice can survive without the H-ras or N-ras genes (or even both of them) but usually die if K-ras is deleted. These mice, despite lacking K-ras, were viable and lived to a ripe old age.

This important observation provides novel opportunities to probe the mechanisms of cancer initiation. Are the mice lacking K-ras now resistant to the lung and pancreatic cancers that are normally linked to K-ras? If yes, this would indicate a true requirement for the K-Ras protein in lung-cancer development; if not, the focus would switch to regulation.

A straw poll of Ras cognoscenti suggests that opinion is for now divided, but my group and others are working on this mouse model, and hope to have answers soon.

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The Scripps Research Institute, La Jolla, California, USA

A biochemist considers whether protein misfolding plays a part in type II diabetes.

Much of my research is on cellular protein folding, and in particular on how protein misfolding or protein aggregation causes disease. My group has developed therapies for a spectrum of misfolding diseases, most of which are associated with neurodegeneration, such as Alzheimer's.

But we are beginning to appreciate that therapies that affect protein folding could have a role in treating a much wider spectrum of diseases than is currently realized.

A compelling article from Gokhan Hotamisligil and his colleagues at Harvard University (U. Özcan et al. Science 313, 1137–1140; 2006) presents one example. They found that mice that are both obese and diabetic benefit from treatment with drugs that enhance protein folding.

Their experiment was motivated by observations that linked obesity and diabetic insulin resistance to stress in the endoplasmic reticulum (ER), a compartment in cells where a third of all proteins are folded.

The researchers gave their fat, diabetic mice chemicals that enhance protein folding in the ER. The effect was notable: the mice's blood-sugar levels fell, they showed increased glucose tolerance and reduced lipid accumulation in the liver.

This suggests to me that protein misfolding may be at the heart of type II diabetes, the age-related disease for which these mice are a model.

Folding of the insulin receptor is inefficient. So it seems reasonable to speculate that cells could become insulin-resistant because of compromised insulin-receptor folding in the ER.

We may find, as we develop more selective small molecules to enhance ER folding, that we discover other disorders that can be treated in this way.

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Harvard University, Cambridge, Massachusetts, USA

Thanks to the discovery of a new catalytic RNA, a chemical biologist can satisfy his student's curiosity.

An first-year undergraduate recently asked me a remarkable question: are all natural ribozymes, RNA molecules with catalytic activity, simply leftovers from the 'RNA world'? The RNA-world hypothesis supposes that RNA molecules were precursors to the first primitive forms of life, before the evolution of DNA and proteins.

Unanswered, my student's question preoccupied me until I encountered a recent paper by Jack Szostak of Massachusetts General Hospital, Boston, and his co-workers (K. Salehi-Ashtiani et al. Science 313, 1788–1792; 2006).

Prior to this work, only two of the known natural ribozymes were associated with mammals. The rarity of catalytic RNAs in more recently evolved, higher-order cells could reflect their attrition on the evolutionary battlefield during the rise of more highly functional protein enzymes.

This paper, however, supports a different conclusion. Szostak's group designed an ingenious system to isolate self-cleaving RNA molecules from RNA encoded in the human genome. Using this system, they discovered several new ribozymes.

One of these ribozymes, associated with a gene known as CPEB3, is highly conserved among placental mammals and marsupials, but is absent from non-mammalian vertebrates. This observation suggests that it arose relatively recently, around 200 million years ago.

We can therefore infer that some ribozymes have evolved in modern organisms, long after the era of the RNA world. The work elegantly demonstrates a new approach to the study of ancient molecules — and also reminds me that our youngest students can ask some of the best questions.

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University of Toronto, Canada

The molecular dance of a protein allows a chemist's secret wish to come true.

One fascinating aspect of molecular function is the way information propagates between parts of a molecule that can be many tens of angstroms apart.

Our understanding of how proteins do this, a process termed allostery, emerged from Max Perutz's pioneering studies of oxygen-carrying haemoglobin. Three-dimensional images show that when a ligand binds to part of the molecule, a discrete set of structural changes take place at distinct sites. This, in turn, influences the ease with which subsequent ligands bind.

Nature has chosen this model in designing many allosteric proteins. However, as a practising nuclear magnetic resonance (NMR) spectroscopist with a strong interest in protein dynamics, I was secretly hoping she might design proteins in which information is communicated through changes in the dynamics between distal sites, with little or no change in overall structure. Moreover, I was rooting for NMR to play a major role in characterizing such a system.

How exciting it was, therefore, to read that Charalampos Kalodimos and his co-workers recently found such a case by studying the motional properties of a protein in different ligated states (N. Popovych et al. Nature Struct. Mol. Biol. 13, 831; 2006). Using NMR spectroscopy, the team quantified protein dynamics for a wide range of timescales. Remarkably, ligand binding at one site is linked to changes in motion far removed, over the complete set of timescales, while a corresponding propagation of structural changes does not occur.

The work of Popovych et al. provides a striking example of the importance of protein dynamics to information transfer. I eagerly await the discovery of more molecular dances and of how they, too, will relate to biological function.

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University of Oxford, UK

A physiologist discusses matters close to the heart.

This time last year my father was suffering from congestive heart failure. He became increasingly frail, slowing down like an unwound clockspring until, in February, his heart simply stopped.

As a physiologist, I had some idea of his condition, but I did not then realize how close it was to my own research area.

In 1983, ATP-sensitive potassium (K-ATP) channels were found in the heart. These channels are gated pores that control potassium fluxes across the cell membrane. However, their precise role in the heart was unclear.

One year later, I discovered that these channels are central to the mechanism by which glucose stimulates insulin secretion from the pancreas. Unravelling the role of K-ATP channels in diabetes, and the way in which channel structure influences function, has been an all-consuming passion for me ever since.

To my surprise, it now turns out that these channels also play a role in heart failure. Heart failure is usually caused by narrowing of the arteries, which increases the pressure against which the heart has to pump, making it work harder. Eventually, it fails.

Recently, Andre Terzic of the Mayo Clinic in Rochester, Minnesota, and his group showed that K-ATP channels confer protection against heart failure (S. Yamada et al. J. Physiol. Lond. published online doi:10.1113/jphysiol.2006.119511; 2006). In normal mice, cardiac K-ATP channels open in response to an increased pressure load, reducing stress on the heart. Mice lacking K-ATP channels rapidly develop heart failure and die.

In the pancreas, K-ATP-channel activity is finely balanced: too much causes diabetes and too little hyperinsulinism. But in the heart, as this paper shows, opening is almost always beneficial.

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