Max Born Institute for Nonlinear Optics and Short Pulse Spectroscopy, Berlin

A physicist discusses how to visualize a molecule changing shape.

It is the dream of many a chemist to watch a movie of a molecule undergoing structural change. So how can we achieve this? One way is to use the relationship between a molecule’s absorption spectrum and its structure to deduce how the structure changes over time. However, a drawback of this technique is its reliance on prior knowledge of the molecular absorption spectrum.

Faton Krasniqi at the Max Planck Advanced Study Group in Hamburg, Germany, and his co-workers present an alternative idea: using photoelectrons ejected from molecules excited by X-ray free-electron lasers to determine molecular structures that change over time (F. Krasniqi et al. Phys. Rev. A 81, 033411; 2010).

They explain how electrons that are ejected and directly detected without any further interaction with the molecule interfere with electrons that scatter off the surrounding atoms in the molecule, thereby creating holographic patterns. These patterns encode the molecule’s three-dimensional structure. As an example, the researchers present calculations through which they reconstruct the six-membered phenyl ring in a chlorobenzene molecule.

This approach of holographic structure retrieval promises powerful insight into time-dependent molecular dynamics in the next few years. It is an idea that is well founded in earlier experiments at synchrotrons. Many of the required experimental techniques — such as the ability to position molecules in space using moderately intense laser fields — have recently been demonstrated. The Linac Coherent Light Source (LCLS), an X-ray free-electron laser at Stanford University in California, has been up and running since last year. Now it’s showtime!

Santa Fe Institute, New Mexico

A theoretician ponders what physics has to offer ecology.

Many species are concentrated in biodiversity hot spots such as tropical rainforests and coral reefs. But our estimates of how many species these and other ecosystems contain are very rough. Conservation efforts and ecological theories would be better served by a more accurate picture.

Our best guesses come from empirical species–area relationships, which count the number of species observed as a function of geographical area. These relationships show sharp increases at local and continental scales, but slow growth at intermediate scales. Despite decades of study, ecologists have no clear explanation of this pattern’s origins or what causes deviations from it.

James O’Dwyer and Jessica Green at the University of Oregon in Eugene recently developed a spatially explicit stochastic model of species birth, death and dispersal that can be solved mathematically using techniques from quantum field theory (J. P. O’Dwyer and J. L. Green Ecol. Lett. 13, 87–95; 2010). Amazingly, the model predicts a species–area relationship that agrees with decades of empirical data, without including ecologically important factors such as body size, predation, habitat or climate.

The work both solves a long-standing mystery and exemplifies a good null model. Because the model includes only neutral mechanisms (birth, death and dispersal), deviations can be interpreted as evidence of non-neutral, ecologically significant processes. It also shows the value of shifting the focus from small-scale, context-dependent processes to large-scale neutral dynamics, a perspective more common in physics than biology.

The model and its shift in perspective could shed light on the immense, important and increasingly studied world of microbial ecologies, which is even more mysterious than those of rainforests and coral reefs.

Yale University, New Haven, Connecticut

An evolutionary geneticist looks at how small genetic changes can have big evolutionary effects.

Vertebrates are diverse in both form and function. What genetic alterations underlie this diversity? Evolutionary modifications in brain size or limb length, for example, involve changes in the complex developmental processes that give rise to these structures. Work in fish elegantly illustrates how a single genetic change can have profound effects on morphological evolution.

David Kingsley at Stanford University in California and his colleagues focused on threespine sticklebacks (Gasterosteus aculeatus), which exist in both marine and freshwater ecosystems (Y. F. Chan et al. Science 327, 302–305; 2010). Most bear pelvic spines on their underside; however, several freshwater populations have lost these structures.

In previous work, the authors suggested that the gene Pitx1 is involved in pelvic reduction in these fish. Now they show that deletion of a sequence that activates Pitx1 expression in the pelvis is directly responsible for the loss of pelvic spines in sticklebacks. In a simple but powerful experiment, they demonstrate that introducing the Pitx1 gene to these pelvic-reduced fish, under the control of the intact Pitx1 regulatory element, is sufficient to restore pelvic spines.

The Pitx1 regulatory deletion has occurred independently in at least nine stickleback populations. This may be because the Pitx1 regulatory element is in a particularly fragile region of the genome that is prone to deletion. Moreover, population-genetic evidence suggests that this recurrent loss of Pitx1 pelvic expression confers a strong fitness advantage — possibly because insects that prey on sticklebacks can grab onto pelvic spines.

This study illustrates the power of laboratory genetics in understanding evolutionary mechanisms, and by doing so provides a conceptual basis for future functional studies of the evolutionary process.

VIB–Catholic University Leuven, Belgium

A cancer geneticist looks at the link between small RNA molecules and cancer.

My laboratory studies how cancer cells evade the action of tumour-suppressor (TS) genes. For most TS genes, both copies must be lost to facilitate tumour progression. For some, haploinsufficiency — loss of only one copy — may also contribute to carcinogenesis. However, selection generally favours the inactivation of the remaining functional gene copy to accelerate cancer pathogenesis.

Now, an additional class of haploinsufficient TS genes has been identified. Tyler Jacks at the Massachusetts Institute of Technology in Cambridge and his team found that loss of one copy of the gene Dicer1 enhanced tumour formation in a mouse model of lung cancer, but selection strongly disfavoured loss of both copies (M. S. Kumar et al. Genes Dev. 23, 2700–2704; 2009). Publicly available data reveal that in one-third of human tumours only one copy of DICER1 is deleted.

This finding has several profound implications for cancer mechanisms and therapies. Dicer1 codes for an enzyme involved in the generation of microRNAs, short fragments of RNA that silence specific genes. The study provides mechanistic insight into the long-standing observation that microRNAs are often downregulated in human tumours. Perhaps more importantly, the data strongly indicate that Dicer1 — and, by extension, a subset of microRNAs — are in fact required for tumours to survive and/or grow. Further studies aimed at deciphering the dependency of tumours on Dicer1 or microRNAs should therefore lead to exciting therapeutic possibilities.

Meanwhile, this class of TS genes, for which partial loss is advantageous to tumours but complete loss is disadvantageous, must not be overlooked in the ever-growing number of high-resolution analyses of mutations found in cancer.

Trinity College Dublin

A neurodevelopmental geneticist explores how one mutation can lead to multiple diseases.

Work in psychiatric genetics has revealed that certain deletions or duplications of small chromosomal regions — termed copy-number variants (CNVs) — drastically increase the risk of disorders such as autism and schizophrenia. The findings are contributing to a shift in how we think about the cause of disease: away from a model involving a combination of common gene variants in each individual to one in which single, rare mutations in any of a large number of genes lead to disease in a high proportion of people.

However, it has come as a major surprise that many such mutations increase the risk not just of one disorder but of many — suggesting that primary insults to neural development may manifest themselves differently from one individual to another.

Evan Eichler at the University of Washington in Seattle and his colleagues investigated one possible reason: genetic background effects (S. Girirajan et al. Nature Genet. 42, 203–209; 2010). Previous studies had identified CNVs at a specific location on chromosome 16 in patients with autism or schizophrenia. Eichler et al. found that such mutations are also enriched in patients with developmental delay or cognitive disabilities.

Interestingly, among these cases, the researchers found a sixfold increase in the occurrence of a second CNV in other parts of the genome. Notably, these patients had a different set of symptoms from those with either single CNV alone.

This kind of modifying effect — due to additional, rare mutations in the background — is probably typical in human biology. With a growing understanding of the observable effects of mutations, it will be important and, in the near future, feasible to take each individual’s entire genetic make-up into account when studying the roots of psychiatric disease.