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.

A quantum mechanic considers how we might ‘talk’ to aliens

So it finally happens. After hundreds of years of humans attempting to communicate with extraterrestrial beings, our descendants receive a message back. But it looks like utter gibberish. What to do? Earthlings might, for example, find some middle ground by sending the aliens a stream of circularly polarized photons to explain what we mean by left handedness. Or maybe the aliens would be able to decipher simple mathematical formulae, encoded in a binary alphabet, through which we could gradually build up a mutual understanding of mathematics, logic, and so forth?

That might work, but what if the replies are still nonsensical? Brendan Juba and Madhu Sudan recently supplied a mathematically precise answer to this question (B. Juba and M. Sudan Symp. Theor. Comput. 123–132; May 2008). Using the theory of interactive proofs, which shows how parties who possess different pieces of a theorem’s proof can cooperate to construct a full proof, they show that as long as aliens are not completely indifferent to communications from Earth, we will quite quickly be able to ascertain whether or not they have knowledge that is useful to us.

The technique that Earthlings should use goes like this: Bob, the human, systematically encodes questions about a class of problems in a form that any computer can interpret. He then repeatedly sends the encoded questions to Alice, the alien, and carefully parses the apparent gobbledygook that she sends back. Juba and Sudan prove that if Alice knows the answers to Bob’s questions (that is, were the questions asked in her own language), and actually answers some non-neglible fraction of those questions (again, in her own language), Bob can determine what she means.

So communicating with aliens is possible in principle, no matter how unpromising the task may seem. I find that reassuring.

A microbiologist learns that all marine creatures must suffer for the greed of a few.

Phosphate is an essential nutrient for all forms of life. Demand for it tends to outstrip supply to such an extent that it limits the overall productivity of many ecosystems, including vast tracts of the seas. I study the curious strategies by which creatures obtain sufficient phosphate for life as they know it.

Some microorganisms, for instance, keep a phosphate store for when times are hard. They scavenge for the nutrient in their surroundings with high-affinity uptake systems and then produce polyphosphate, an insoluble polymer that packs hundreds of phosphate subunits into a single strand. Strands of polyphosphate then form intracellular granules that can be broken down by cellular enzymes when they are needed.

This kind of 'luxury' uptake was recently the focus of a study by Ellery Ingall of the Georgia Institute of Technology in Atlanta and his colleagues. Diatoms — unicellular, silica-walled algae — accumulate phosphate during summer blooms to levels far beyond their immediate needs. Indeed, polyphosphate produced by plankton accounted for 7–11% of the total phosphate in the surface waters of Effingham Inlet, a fjord on Vancouver Island, Canada (J. Diaz et al. Science 320, 652–655; 2008).

This self-indulgent behaviour seems to have far-reaching consequences. Decaying plankton eventually sink to the ocean floor, where they spill unused polyphosphate onto the sediment surface. Notably, Ingall and his team found that soluble phosphate was not released at this point. Instead, polyphosphate molecules seeded the precipitation of minerals called apatites, a process that took only a few years. So diatom greed may ultimately lower the ceiling on marine productivity by locking away the oceans' most hard-to-come-by nutrient. That is important as well as curious.

A palaeobiologist calls for greater biological realism in climate models.

The world's most sophisticated climate models fail to adequately replicate climate at high latitudes and over continents' interiors during ancient periods of greenhouse-gas-induced warming: the wintertime predictions are consistently too cold. This makes me worry that the field is missing fundamental feedback processes that amplify warming. If so, climate models might be underestimating how much anthropogenic warming will happen in the future.

What might these mysterious processes be? Lee Kump and David Pollard of Pennsylvania State University in University Park think they have found one. They propose that marine phytoplankton that emit dimethylsulphide — already recognized as a major source of cloud-seeding particles far out to sea — became thermally stressed during the Cretaceous period (100 million years ago). As a result, the phytoplankton grew more slowly and reduced their emissions. Fewer biologically derived aerosol particles meant fewer nuclei for cloud condensation, which, in turn, led to less extensive cloud cover and more transparent clouds. Solar radiation was thus reflected less, and polar temperatures rose by 10–15 °C (L. R. Kump and D. Pollard, Science 320, 195; 2008).

Kump and Pollard's work is exciting for its dramatic result. Nevertheless, the duo's findings are ultimately unsatisfactory; the effects of heat on biological aerosol emissions need to be better described in their model for it to generate really solid conclusions. Although some recent field and laboratory experiments do suggest that marine algae produce less dimethylsulphide when carbon dioxide concentrations approach those of the Cretaceous, much more research is needed. If such results agree with Kump and Pollard's assumptions, I might worry less about climate models — but maybe even more about global warming.

An epidemiologist points to a fifth sort of human malaria.

Malaria has plagued humans since the dawn of written history, and probably since long before that. These days, biologists understand tiny mechanistic details of the workings of one human malarial parasite, Plasmodium falciparum, but know surprisingly little about the others. As someone who studies how pandemics are born and die — and how they might one day be prevented — these holes in our knowledge seem striking to me.

Aside from P. falciparum — the cause of 'malignant' malaria — parasitologists acknowledge three other human malaria parasites, P. vivax, P. ovale and P. malariae, each of which probably jumped from another primate host to humans independently. With so many malaria parasites plaguing other vertebrate species, however, and only basic diagnostic instruments available in most parts of the world, science could be missing new types of human malaria that have the potential to seed pandemics.

In a recent paper, Janet Cox-Singh and her colleagues build on their earlier finding that humans can harbour a fifth malaria parasite, P. knowlesi, which was once thought to infect only Asian monkeys. The researchers detected P. knowlesi DNA in about one third of 1,014 malaria patients in Malaysia, showing that this parasite is common, deadly and almost always misidentified as P. malariae (J. Cox-Singh et al. Clin. Infect. Dis. 46, 165–171; 2008).

That an unknown animal pathogen can cause widespread human disease is reminiscent of some of the biggest scourges of the twentieth century: HIV and pandemic influenza. Reductionist, molecular approaches to tackling important plagues may be en vogue and a near necessity for grant funding, but I bet that an old-fashioned natural historian studying how infectious agents jump host species will be first to signal the coming of the next plague.

A zoologist traces flu across the globe.

In winter, everybody recognizes a stuffy nose, a fever and an achy body as influenza. But experts still grapple with where the flu virus goes during the summer. One theory has it that flu lays low, holding out until the following season in a small number of asymptomatic people. Another idea — that flu strains tend to become extinct locally but shift around geographically — carries more weight. A recent paper by Derek Smith of the University of Cambridge, UK, and his colleagues helped nail the latter hypothesis by plotting the results of antigen-binding assays and genetic sequencing of more than ten thousand viruses on a map (C. A. Russell et al. Science 320, 340–346; 2008).

The researchers call this approach 'antigenic cartography'. Their antigenic time charts contain data crunched from the portion of the World Health Organization's enormous 'Global Influenza Surveillance Network' database that details strains classified as 'H3N2' between 2002 and 2007. First, they confirm flu's source–sink dynamics by showing that winter flu strains are more closely related to (and thus more likely to have evolved from) strains found elsewhere than to last season's local contagion. Second, the team pinned down H3N2's spread. Temperate regions are regularly seeded by strains from east and southeast Asia, where many strains circulate continuously and asynchronously in a pattern probably driven by varying climatic conditions.

These findings suggest that close surveillance of emerging strains in east and southeast Asia could enable us to predict those that will later affect the rest of the world. Yet it also poses a question: why do flu strains not return to this region after spending time (and thus evolving) elsewhere? Now that we know where new strains come from, we need to find out why they never go back.

An evolutionary biologist considers the virulence of emerging infectious diseases.

When a pathogen — for example, HIV — emerges into the human population, it adapts to growth and transmission in human hosts. At the same time, its virulence (often measured by case mortality) typically changes as well. On the basis of theoretical arguments and examples such as the myxoma virus, conventional wisdom holds that if a disease is highly virulent at first, it will rapidly evolve reduced virulence so as to maximize transmissibility. The idea is that pathogens face a virulence–transmissibility trade-off: strains that kill or even incapacitate their hosts are unlikely to spread as broadly as those that keep their hosts alive and mobile.

One might think — and some have argued — that we can take comfort from such reasoning. By this logic, the 60% mortality rate seen in human cases of H5N1 avian influenza should rapidly attenuate were a human pandemic to occur. But in the inaugural issue of Evolutionary Applications, Bull and Ebert refute this thinking using a clear, simple mathematical model (J. J. Bull & D. Ebert Evol. Appl. 1, 172–182; 2008).

As someone working on the dynamics of emerging infectious diseases, I find this paper fascinating and sobering in equal measure. The gist of its argument is that trade-off models may not apply well to emerging infectious diseases, precisely because they are still emerging. When a disease first enters a new host, it can be far from the optimum point on the virulence–transmissibility trade-off curve. Its early evolutionary trajectory may be contingent on mutation supply and thus very hard to predict: virulence might decline, but could also initially rise.

The implications are clear. We need to invest now in disease surveillance, public-health infrastructure and pandemic planning. We cannot count on evolution to do our work for us.

A population geneticist looks back in time in search of human origins.

When and where anatomically modern humans evolved is arguably one of the most fundamental scientific questions. The issue also has philosophical and possibly even moral implications because it influences our definition of humanity. But I became involved in the subject for much more prosaic reasons. I was trying to make sense of the distributions among human populations of different versions of genes that imbue resistance to infectious diseases. It struck me that attempting to do this without a clear understanding of humans' past demography was bound to end in a muddle.

Despite decades of research, the origin of modern humans is still hotly debated. In a recent paper, Laurent Excoffier and his colleagues provide the first formal statistical evaluation of the likelihood for the various schemes that have been proposed (N. J. R. Fagundes et al. Proc. Natl Acad. Sci. USA 104, 17614–17619; 2007). They conclude that a recent expansion from a single African origin is better supported by the current geographical spread of human genes than a multi-regional scenario. The multi-regional hypothesis proposes that modern humans hybridized with archaic humans, such as Homo erectus, as they spread.

This result may seem unsurprising because most genetic evidence points to an African origin some 60,000 years ago with no or negligible hybridization with archaic humans. However, there is a twist. By far the best supporting evidence for hybridization between modern and archaic humans has been the observation that, looking back, the amount of time it takes to reach the most recent common ancestor of some genes largely predates the age of our species. The extensive simulations in this paper debunk that argument by demonstrating that such cases can arise if modern humans had a recent and single African origin.

A biologist looks to 'click chemistry' for better three-dimensional tissue models.

A hot topic in organic chemistry is the development of ways to neatly home in on a particular chemical group and cause a reaction to proceed extremely efficiently under mild conditions. Such highly optimized reactions have been grouped under the term 'click chemistry'. A commonly cited example involves functional groups called azides and alkynes, which react to form triazoles with the aid of a copper catalyst.

Click chemistry has all sorts of uses, although few are in biology because the technique relies on toxic metal catalysts. However, Carolyn Bertozzi and her colleagues at the University of California, Berkeley, and the nearby Lawrence Berkeley National Laboratory recently demonstrated copper-free click chemistry in a living system (J. M. Baskin et al. Proc. Natl Acad. Sci. USA 104, 16793–16797; 2007). These authors selectively — and rapidly — labelled cell-surface polysaccharides with with triazole bound to a fluorescent probe. The technique allows real-time imaging of cell surface molecules that are otherwise impossible to achieve.

This research throws open the door for a host of new applications for click chemistry. As a tissue engineer, I am particularly excited about exploiting it to make better gels for three-dimensional cell culture.

Physiological processes are routinely guided by interactions between cells and their tissue environment. Thus, a major hurdle in tissue regeneration is knowing which biochemical signals must be recapitulated in cell culture, and how to present them at the appropriate time and place. Copper-free click chemistry could allow scientists to synthesize materials that deliver these signals at times that are governed by the physiological conditions in which the material resides. Next on my wish list is the ability to control the spatial organization of these reactions.

An immunologist muses about inflammation through cell interactions.

I spend my lab hours trying to understand what prompts T cells — a type of white blood cell — to specialize. Some T cells produce soluble molecules that rattle the immune system into an inflamed state; other cells generate molecules that calm the system back down.

Upon infection, cells such as macrophages — another type of white blood cell — produce soluble molecules called interleukins that direct the fate of the responding T cells. An emerging curiosity in the field is which interleukins make certain T cells become pro-inflammatory, and which cause other T cells to become anti-inflammatory. This decision is crucial for determining whether an immune response induces or suppresses inflammation.

Recently, investigators have turned their attention towards an interleukin known as IL-27. This is produced by activated macrophages and was initially thought to induce IFN, a signalling molecule that activates macrophages even more.

But work by Nico Giraldi and his colleagues at Genentech in South San Francisco, and other groups, has recast IL-27 as a molecule that primarily directs T cells to suppress inflammation. In a paper published in March, Giraldi's team confirmed that IL-27 acts in this way because it causes CD4+ and CD8+ T cells to make the anti-inflammatory IL-10, and does not work through an alternative pathway (M. Batten et al. J. Immunol. 180, 2752–2756; 2008). Mice with Listeria infections or autoimmune tissue inflammation in their brains and spinal cords generated fewer IL-10-producing T cells when they lacked an IL-27 receptor. Whether an analogous interaction occurs in humans is not known, but, if it does occur, this research could become medically useful.

A statistician wonders about the influence of additive variance

Where complex problems are concerned, it makes things simpler if some factors can be safely ignored. In quantitative genetics, one such assumption is that the bulk of genetic variation is additive. That is, the effect of an allele — a particular version of a gene — can be adequately described by its average effect in a population. But we know that genes often do not act additively; alleles interact, both with others of the same gene (a phenomenon known as dominance) and those of different genes (epistasis). All this contributes to the total genetic variation. But does this matter?

This question is tackled by Hill et al. (PLoS Genet. 4, e1000008; 2008). Reviewing the literature, they show that additive genetic variance is often close to total genetic variance. The authors then look at some mathematical models with strong non-additive genetic effects, and average over reasonable distributions of allele frequencies to show that the genetic variance is mainly additive. So non-additive genetic variation is usually of minor significance and we can continue to concentrate on additive genetic variance.

This is probably true on average, but may not always be so. Any trait is affected by only a finite, and in some cases small, number of genes. So averaging over all possible allele frequencies may say little about a particular case. There is also a much subtler problem. The authors conclude that additive genetic variance swamps other types of variation largely because most alleles common to a population occur with close to 100% frequency. But these extreme frequencies also reduce the total genetic variance. So, in practice, a lot of traits with strong additive effects might be classified as having no detectable genetic variation, and overall the importance of additive genetic effects would be diminished. Is this a genuine problem? Ah, more research is obviously needed.

A signalling scientist marvels at perfect patterns

The formation of patterns during animal development depends to a great extent on cells, or groups of cells, sending a specific signal that activates a cascade of reactions in the cells that receive and respond to it. Studies of this process in the fruitfly Drosophila have provided many insights into the nature of the molecules involved and the mechanisms underlying cell–cell signalling.

The cell surfaces of almost all animals are decorated extensively with large molecules known as heparan sulphate proteoglycans (HSPGs). These modulate most developmental signalling pathways and comprise protein cores modified by the addition of long carbohydrate chains called glycosaminoglycans (GAGs). GAGs are key to mediating interactions between HSPGs and the molecules that they bind.

Recently, Rahul Warrior at the University of California, Irvine, and his colleagues (Development 135, 1039–1047; 2008) explained the puzzling observation that although HSPGs are required for signalling by the protein BMP in certain tissues, they are not required for BMP signalling during very early fly development.

The authors demonstrate that GAG synthesis does not occur in early embryos because the messenger RNAs that encode two enzymes involved in its construction are not translated.Preventing GAG synthesis at this stage allows an 'activity gradient' of BMP to be generated across the embryo that patterns the dorso–ventral axis of the fly. A few hours later, the GAG enzymes are produced, allowing the modified HSPGs to participate in other signalling pathways.

This study illustrates how temporal control of the synthesis of a ubiquitous set of enzymes is used to modulate the activity of signalling pathways in different tissues.

A chemist looks at DNA-based molecular logic

Logic gates — AND, OR and NOT gates — are used in all manner of electronic devices, for example computers, in which they are connected in huge arrays. Several research groups, including my own, have designed and built molecular logic gates since the early 1990s. But the usefulness of our efforts has been limited because linking these gates in series has proved difficult.

Recently, Reza Ghadiri and his colleagues at the Scripps Research Institute in La Jolla, California, constructed a full set of logic gates that release a single-stranded DNA sequence when provided with the correct combination of single-stranded DNA inputs (B. M. Frezza et al. J. Am. Chem. Soc. 129, 14875–14879; 2007). This means that the output of one gate can be the input for another, and that the gates can be 'wired together' into multi-level circuits using the solution containing the DNA as a communication medium.

The gates work as follows. When a single strand of DNA pairs with a longer strand, an 'overhang' of unpaired DNA is left. If another complementary strand then comes along that is the same length as the longer strand, the overhang provides a foothold, allowing the new strand to push the shorter one off and form a full-length hybridized pair. Ghadiri et al. attached the DNA to beads so that different gates could be kept apart until the correct input was ready. They also added a fluorescent part to the final output signal to make the result easy to monitor.

This may not seem like much of an achievement to a computer buff. Nevertheless, I think the principle that this paper describes could pave the way to more useful molecular logic gates. In the meantime, the simple molecular logic gates that are available can serve in real-life applications such as identification tags for small micrometric objects. Semiconductor identification devices are too big for this purpose.

A physicist applauds evidence for the quantum spin Hall effect

I have been fascinated by the ballistic (collisionless) motion of charge carriers in solids since the start of my career. In practice this motion is often impeded by unavoidable impurities in the solid. But when it works, the charge carriers maintain their quantum properties while dissipating a minimum amount of energy.

Applying a strong magnetic field perpendicular to a two-dimensional conducting layer can accomplish the feat. Then, the quantum Hall effect kicks in, forcing the charges to the edges of the sample where they skip along in so-called 'chiral edge channels'. Backward scattering is virtually eliminated because that would require the charges to find a way to the opposite edge, where charges move in the opposite direction.

Recently, Laurens Molenkamp of the University of Würzburg in Germany and his colleagues took a step towards verifying the quantum spin Hall effect (M. König et al. Science 318, 766–770; 2007). This is where chiral edge channels form spontaneously in semiconductor insulators with peculiar electronic structures — namely, where the valence band is energetically higher than the conduction band because of the strong spin-orbit interaction between electron spins and electron velocities. This means that spin-up electrons are carried only by edge channels moving in one direction and spin-down elections are carried by edge channels moving in the opposite direction.

Molenkamp's team used a thin layer of mercury telluride sandwiched between two layers of mercury cadmium telluride. Because measuring spin current is difficult, they recorded the conductance of this middle layer to verify the ballistic transport that characterizes edge-channel transport. It was quantized, as predicted.

With further verification, the finding could lead to low-power devices based on the transport of spins rather than charges. Thus a quirk in the scientific field I have always loved might find a practical application.

A synthetic chemist takes inspiration from sketching structures.

I enjoy drawing chemical structures of complex natural products and imagining how their polar functional groups, such as –OH and –NH2, interact with biopolymers. I usually first draw a carbon framework of the molecule on paper and then add the required groups. Of course, this order of 'functionalizations' has almost nothing to do with any synthetic scheme I might use for that molecule. Tedious multi-step manipulations are often needed just to introduce one oxygen or nitrogen. Making a molecule will never be as easy as drawing one.

Many research groups are trying to make it easier by devising one-step introductions of complete polar groups into carbon frameworks. One of the latest examples comes from Mark Chen and Christina White (Science, 318, 783–787; 2007). They used a new iron catalyst and hydrogen peroxide to convert specific hydrogens to hydroxyl groups on the carbon skeletons of a variety of molecules.

The catalyst seems to be able to differentiate a site of functionalization from other potentially oxidizable C–H bonds by the balance of two factors: electron-richness and steric accessibility of the bond. Chen and White were able to oxidize the antimalarial natural product (+)-artemisinin at just one predicted position to produce (+)-10-(beta)hydroxyartemisinin. Their work represents a definite advance in the direct functionalization of carbon skeletons.

Every chemist dreams about placing functional groups anywhere they want as easily as drawing them on paper. The direct C–H oxidation reaction should allow us to perform such manipulations and holds great promise for simplifying the synthesis of complex molecules.