Swiss Federal Institute of Technology, Lausanne

A chemist highlights promising organometallic drugs.

Traditionally, the compounds we use to fight cancer come in two flavours. Inorganic drugs, such as cisplatin — a small molecule with a platinum core — are the workhorses of chemotherapy. They are generally highly toxic to cells, not particularly selective, and are accompanied by side effects ranging from vomiting to kidney damage. Larger organic drugs offer a more targeted but weaker approach. They can selectively pick off key enzymes, but may work on only a narrow range of cancers.

In the search for more effective anticancer weaponry, hybrids of inorganic and organic components — organometallic drugs — are increasingly important. Once thought of as unstable, highly toxic species, these compounds are now being developed by chemists to treat a broad range of tumours and to overcome platinum-resistant cancer cells. Like organic drugs, they have a selective mode of action and so cause fewer side effects.

The dinuclear ruthenium-arene compounds trialled by Bernhard Keppler of the University of Vienna and his colleagues are promising examples (M. G. Mendoza-Ferri et al. J. Med. Chem. 52, 916–925; 2009). These highly cytotoxic compounds contain two ruthenium centres, separated by an adjustable organic linker. By tweaking the length of this chain, the researchers produced compounds that are as active as established platinum-based drugs in human tumour-cell lines.

What's more, the ruthenium drugs could kill tumour cells that were resistant to oxoplatin, a drug related to cisplatin. They work by linking DNA duplexes together, and can also bind histone proteins to DNA.

The compounds have now progressed to experiments in animals. By reducing side effects, I hope the drugs can improve the quality of life for patients undergoing chemotherapy.

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Harvard Medical School

A geneticist views two theories of X-chromosome inactivation in a broad context.

Female mammals have two X chromosomes, one of which is inactivated to ensure that females get the same dose of X-linked genes as males. Two long, non-coding RNA molecules mediate this process. One, Xist, initiates silencing of the chromosome to be inactivated, whereas its antisense partner, Tsix, blocks such silencing of the remaining X. The exact mechanism by which Xist and Tsix exert their functions is not known.

RNA interference (RNAi) describes a process by which RNA fragments 'interfere' with the creation of proteins from their RNA recipes. The recent discovery of RNAi in mammalian cells made it tempting to postulate that sense and antisense non-coding RNA partners, such as Xist and Tsix, are processed by the RNAi-associated enzyme DICER into small RNAs. Jeannie Lee and her team at Harvard Medical School have presented several lines of evidence in support of this, including data that demonstrate improper X inactivation in DICER's absence (Y. Ogawa et al. Science 320, 1336–1341; 2008).

By contrast, a study by David Livingston of Harvard's Dana-Farber Cancer Institute and his colleagues has shown that, in the absence of DICER, the inactive X chromosome in stem cells remains coated with Xist and several other repressive markers (C. Kanellopoulou et al. Proc. Natl Acad. Sci. USA 106, 1122–1127; 2009). This group suggests that the effects observed by Ogawa et al. may have been indirect because DICER is also involved in the processing of a class of small, non-coding RNAs known as microRNAs that can alter gene expression by fine-tuning protein production.

Despite their differences, these studies should provide an incentive to further investigate the potential role of the RNAi pathway in the nucleus of mammalian cells. This will shed light on both X inactivation and gene regulation in general.

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Massachusetts Institute of Technology

A theoretical physicist examines exotic particles lurking in new materials.

Axions are very light, very weakly interacting particles, whose existence was posited more than 30 years ago [1,2] in order to clean up our ‘standard model’ of particle physics [3]. They close an annoying loophole in Kobayashi and Maskawa’s Nobel-prize-winning explanation of why the microscopic laws of physics look so nearly the same when running backwards as forwards in time (time reversal symmetry).

Despite heroic efforts — and several false alarms — axions have not yet been detected, but they have become increasingly important. They have been warmly embraced in unified field theories and in string theory. And when we run the equations through Big-Bang cosmology, we find that axions should contribute much of the dark matter that astronomers have inferred to explain the Universe [5].

Now Shou-Cheng Zhang and his colleagues (X.-L. Qi et al. Phys. Rev. B78, 195424; 2008) inform us that, all along, axions have been lurking unrecognized on surfaces of bismuth-tin alloys and other materials. To be more precise: the equations that arise in axion physics [6,7] are the same as those that describe the electromagnetic behaviour of a recently discovered class of materials known, collectively, as topological insulators [8,9].
The axion field inside topological insulators is an emergent — and subtle — property of collections of electrons that is connected to their spin–orbit coupling.

These ‘quasi-axions’ don’t improve our standard model, but they do have the charming advantage of being accessible, possibly even useful. There are ideas to exploit their behaviour to make anyons [10], potential building blocks for quantum computation.

No short summary can do justice to the wealth of ideas synthesized in this paper. Powerful, beautiful mathematics is at play in reality.

1. Weinberg. S. Phys. Rev. Lett. 40, 223 (1978).
2. Wilczek, F. Phys. Rev. Lett. 40, 279 (1978).
3. Peccei, R. & Quinn, H. Phys. Rev. Lett. 38, 1440 (1977)
4. Svrcek, P. & Witten, E. J. High Energy Phys. 0606 (2006).
5. Hertzberg, M., Tegmark, M. & Wilczek. F. Phys.Rev. D78, 083507 (2008).
6. Huang, M. & Sikivie, P. Phys. Rev. D32, 1560 (1985).
7. Wilczek, F. Phys. Rev. Lett. 58, 1799 (1987).
8. Kane, C. & Mele,E. Phys. Rev. Lett. 95, 226801 (2005).
9. Fu, L., Kane, C. & Mele, E. Phys. Rev. 98, 106803 (2007).
10. Fu, L. & Kane, C. Phys. Rev. Lett. 100, 096407 (2008).

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University of Manchester, UK

A physiologist notes the similarities between animal and plant electricity.

Almost all organisms run on electricity. As an undergraduate, I was intrigued by the fact that the long, single cells of the freshwater plant Nitella are nearly identical to those of single nerve fibres. These plant cells generate slow action potentials that are similar to those of human or animal nerves. But the electrical components that span plant and animal membranes — the ion channels and transporter proteins — are usually quite different, as are some of the ions they transport.

Earlier this year, however, two researchers in Italy found that a single mutation can turn an important transport protein from a component that is compatible with animal electrical systems into one that is appropriate for plants. They studied the protein CLC-5, which is abundant in the intracellular vesicles of kidney cells. There, it exchanges chloride ions for protons, and in so doing regulates the vesicles' acid content (G. Zifarelli and M. Pusch EMBO J. 28, 175–182; 2009).

The researchers knew that CLC-5 resembled the plant transporter atCLCa, but they had no idea how closely. In plant vacuoles, which are formed by the fusion of several vesicles, atCLCa exchanges not chloride but nitrate ions for protons. The difference is vital: nitrate is necessary for plants to grow and is stored in the vacuoles of root and shoot cells, whereas chloride has a very different role. It is needed for photosynthesis and for the opening and closing of stomata, which matters mostly in the leaves.

Merely substituting one serine amino acid in CLC-5 with a proline changed the protein from a chloride transporter into a nitrate transporter. I find this fascinating because it provides an even more striking example of the similarities that animals and plants can share, even though their biologies are generally very different.

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