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.

Posted on July 1, 2009 07:26 PM | Permalink | Comments (0) | TrackBacks (0)

University of Maryland, College Park

A physicist peels back the layers of excitement about graphene.

Graphene is an atom-thick sheet of carbon in which electrons behave as if they have no mass. Atomic carbon layers have been grown epitaxially — that is, perfectly aligned with atoms in an underlying crystal surface — on metals and semiconductors for decades, so why the fuss lately?

Well, in the past few years much work in this field has revolved around graphene obtained by 'exfoliating' or peeling it from graphite. By mounting exfoliated graphene on insulating silicon dioxide, researchers observed a half-integer quantum Hall effect, an anomalous measurement that stems from the existence of a Landau level — the quantized orbit of electrons in a magnetic field — at exactly zero energy, a signature property of massless electrons.

But exfoliated graphene is dirty, lumpy and tiny (the biggest pieces are still a tenth of a millimetre in diameter). I wondered whether the older technique of epitaxial growth could produce a better material. In May, a group led by Joseph Stroscio showed that it could (D. L. Miller et al. Science 324, 924–927; 2009). Using scanning tunnelling spectroscopy to study epitaxial graphene on the surface of silicon carbide in a magnetic field, they showed that epitaxial graphene is extraordinarily clean and flat, and clearly exhibits the zero-energy Landau level. For the first time in any material, epitaxial graphene allows direct observation with atomic resolution of the behaviour of electrons in quantized Landau levels, opening a new window on the quantum Hall effect.

Researchers using other techniques, such as cyclotron resonance and photoemission, are also reporting an astonishingly clean electronic system in epitaxial graphene. Experiments on conductivity remain a challenge, but epitaxial graphene seems to have a bright future.

Posted on June 24, 2009 08:39 PM | Permalink | Comments (1) | TrackBacks (0)

ETH Zürich, Switzerland

An infection biologist points out an outstanding issue in mucosal immunology.

The gut immune system can distinguish between harmless commensal microorganisms and dangerous pathogens, and attenuates its response to the former to avoid dangerous chronic inflammation. The mechanisms that maintain this hyporesponsiveness are just beginning to be unravelled.

Dendritic cells, the key organizers of appropriate immune responses, actively sample commensal microbes. In organs other than the gut, this would trigger a strong immune response, and the responsiveness of intestinal dendritic cells to microbes is thought to be thwarted by anti-inflammatory molecules released by gut cells. But the situation could be much more complex: hyporesponsiveness might be restricted to certain 'microbe-associated molecular patterns' (MAMPs), such as lipopolysaccharides, large molecules attached to the outer membrane of many bacteria.

Linda Klavinskis of Kings College London and her team have analysed the MAMP-responsiveness of dendritic cells migrating from gut tissue to local lymph nodes. Surprisingly, these cells do respond to harmless Bacillus spores and most MAMPs — but not lipopolysaccharides (V. Cerovic et al. J. Immunol. 182, 2405–2415; 2009). Does this suggest that hyporesponsiveness of intestinal dendritic cells is transient? The maintenance of hyporesponsiveness in the gut mucosa, patterns of MAMP-hyporesponsiveness, and localization and timing of MAMP responses will be important topics for future research.

Unfortunately, unactivated dendritic cells are hard to isolate from the gut mucosa. In situ analysis of dendritic-cell responses to gut microbes in intact tissue holds much promise. Technical advances in multicolour two-photon microscopy, fluorescently tagged microbes, and transgenic mice expressing cell-type and response-specific fluorescent reporter proteins will be instrumental in this key area of biology.

Posted on June 17, 2009 07:31 PM | Permalink | Comments (0) | TrackBacks (0)

University of Texas, Austin, USA

A geophysicist ponders the mysteries of intraplate earthquakes.

During my first semester at college, I attended a lecture describing plate tectonics, and immediately knew that geophysics would be my major and hopefully my career. Subsequent lectures, textbooks, journal articles and, later, my own research educated me about how elegantly plate tectonics explains the processes that control the locations of most earthquakes.

However, some of the largest-known North American earthquakes — including those of 1811–12 famed for ringing church bells in Boston and changing the course of the Mississippi River — are associated with the New Madrid Seismic Zone (NMSZ) in the Southern and Midwestern United States, far from known plate boundaries. So what causes these events? Eric Calais of Purdue University in Indiana and Seth Stein at Northwestern University in Illinois present some surprising results from an examination of Global Positioning System (GPS) data from the region (E. Calais and S. Stein Science 323, 1442; 2009).

Previous studies found that the NMSZ was moving at a different rate and in a different direction from the North American Plate, implying that strain would steadily accumulate until released by a large-magnitude earthquake. But, incorporating three years' worth of extra GPS data, Calais and Stein found motions indistinguishable from those of the North American Plate, corresponding to extremely low strain rates. It is not clear what the underlying processes causing the NMSZ earthquakes are. Is strain accumulation variable over time in intraplate settings? What are the implications for hazard prediction?

The results leave me perplexed, but oddly comforted — there are plenty of mysteries left for the next generation of geophysicists. And perhaps one day a theory will elegantly explain intraplate seismicity, just as plate tectonics did for interplate seismicity.

Posted on June 11, 2009 04:39 AM | Permalink | Comments (0) | TrackBacks (0)

Nicholas School of the Environment, Duke University, Durham, North Carolina

An ecologist calls for a citizen-science 'Wiki'.

Where do species occur and why? What happens to ecological communities when species are removed or when alien species invade? And how will the answers shift as climates change? These questions span huge spatial and temporal scales, and involve millions of species. By contrast, ecological field studies are generally of short duration, include few species and cover small areas. This means that getting data for the big questions is a tall order — impossible without harnessing a deeper reserve of people power.

Citizen science — in which qualified scientists oversee volunteers — is not new. The Audubon Society's Christmas Bird Count has run for 108 years and mobilizes about 60,000 volunteers across 1 million square kilometres of North America who count about 58 million individual birds annually. Other citizen-science projects are under way around the world.

Dirk Schmeller at the Helmholtz Centre for Environmental Research in Leipzig, Germany, and his colleagues analysed 395 citizen-science projects across five European countries, involving more than 46,000 participants (D. Schmeller Conserv. Biol. 23, 307–316; 2008). Volunteers donated more than 148,000 person-days per year, a figure inconceivable using professional scientists alone. Schmeller et al. found that volunteer-gathered data are reliable and unbiased, with data quality determined less by 'volunteer' status, and more by survey design and methodology.

The rapid increase in citizen-science data sets can revolutionize what we know about the natural world. Wikipedia has shown that the public is willing to donate time, talent and knowledge, given a sufficient platform. Biodiversity data lack such a platform for input, integration, mapping and dissemination. This is a deficiency that the environmental community should address.

Posted on June 4, 2009 12:32 AM | Permalink | Comments (0) | TrackBacks (0)

Broad Institute, Cambridge, Massachusetts

A biologist looks at new functions for non-coding RNAs.

The increasing study of small and large RNA molecules that do not encode protein — non-coding RNAs — is widening our view of their relevance, and of their roles in important developmental mechanisms such as gene silencing and X-chromosome inactivation. Nevertheless, our knowledge covers only a fraction of the non-coding transcripts produced from the mammalian genome.

Much of the non-coding RNA transcribed is associated with protein-coding genes: for example, the transcripts that are complementary or 'antisense' to the gene sequence. These can be created by 'bidirectional' transcription from either DNA strand. Kevin Morris of the Scripps Research Institute in La Jolla, California, and his colleagues have now shed light on the function of this type of transcription (K. V. Morris et al. PLoS Genet. 4, e1000258; 2008).

They focused on the gene encoding the tumour suppressor p21, transcription of which must be finely tuned, and show that an endogenous antisense transcript of p21 controls the amount of p21 mRNA made by silencing its promoter. This transcriptional suppression is dependent on Argonaute-1, a protein implicated in RNA-mediated gene silencing. Suppression correlates with bidirectional transcription within p21's promoter.

This observation is not limited to p21: a similar regulatory mechanism controls gene expression of the protein E-cadherin, suggesting that this balancing of sense and antisense transcription might be a common mechanism of transcriptional regulation.

The next challenge is to understand how RNAs can induce transcriptional gene silencing; information that will probably reveal just how much power RNA wields in the control of gene expression.

Posted on May 27, 2009 06:22 PM | Permalink | Comments (0) | TrackBacks (0)

Burnham Institute for Medical Research, La Jolla, California

A structural biologist has great expectations for llamas' small antibodies.

Llamas aren't just unusual and exotic looking: their antibodies are also a reason for much excitement. Made entirely of heavy chains, they are about half the size of those found in humans and many other vertebrates, which are normally composed of both heavy and light chains. When it comes to therapeutic applications, these larger antibodies are hard to store and deliver. But llama and other camelid antibodies demonstrate superior heat-stability and solubility, without compromising affinity or specificity, making them an attractive alternative.

Robin Weiss of University College London and his colleagues isolated three llama antibodies, known as 'neutralizing' antibodies, that can broadly prevent multiple HIV subtypes from infecting cells (A. Forsman et al. J. Virol. 82, 12069–12081; 2008). They began by creating an antibody library from two llamas immunized with the HIV gp120 antigen. To select for neutralizing antibodies, antibodies were raised against one HIV subtype but cross-screened against multiple subtypes. The researchers also included a competitive elution step to select antibodies that can compete with binding by CD4, the primary HIV receptor on human T cells. It remains to be seen how these neutralizing antibodies fare in animal studies and where they bind in atomic detail.

Intriguingly, there have been reports of several potent, broadly neutralizing human antibodies (for example, F10 and CR6261 against influenza's haemagglutinin) in which only heavy chains are involved in antigen binding — reminiscent of the situation of llama antibodies. These studies corroborate that the heavy chain alone can mediate broad neutralizing activity, and invite speculation that this may be a special strategy engaged by the human immune system to reach cryptic binding sites. Llama antibodies may be even better suited for those hard-to-reach targets.

Posted on May 21, 2009 01:55 PM | Permalink | Comments (0) | TrackBacks (0)

University of Southampton, UK

A stem-cell researcher considers an accusation of dullness.

How might hard-working scientists react to an accusation that 'modern scientists' are 'dull', as is provocatively postulated in a March editorial of the non-peer-reviewed journal Medical Hypotheses (B. Charlton Med. Hypotheses 72, 237–243; 2009). With offence? Humour? Ambivalence? Or, perhaps, in response to a jeremiad bemoaning our apparent insufficient intelligence and creativity, we might retort, "So what? Tell us something we don't know."

Because, it seems to me, most working scientists have either long since accepted that they are not of the 'revolutionary' type exemplified by greats such as Isaac Newton, Charles Darwin and Albert Einstein, or never strived to be. Gaining and retaining employment in academia is hard enough. Yes, we are of the persevering and conscientious 'normal' type — if we weren't, nothing would get done.

We know there is too much bureaucracy. And yes, there is a lot of repetitive, boring, tiresome, problematic work to be done that is unlikely to shift any paradigms (yet), but important nonetheless. Whether or not somehow creating more windows of opportunity for would-be geniuses possessed of the requisite levels of selfishness and creativity would lead to significant changes in direction is debatable. But the drudge is always necessary in a multidisciplinary collaborative enterprise.

It's not that scientists are dull per se. Rather, instead of being the 'clever crazy' type that might belong in an institution, we labour in an institutionalized occupation that demands we play by certain rules. We know we're not going to change the world, but we like to think we can contribute to the sum of knowledge. Providing we can first convince our peers. If it was easy, everybody would do it. One might add, complaining that modern science can be dull, although valid, isn't exactly a 'revolutionary' idea. Tell us something original, eh?

Posted on May 15, 2009 03:01 PM | Permalink | Comments (0) | TrackBacks (0)