RESEARCH NEWS & VIEWS cancer — the diameter of the tumour and the include changes that reduce the cell’s drive to cells dormant for a longer, but still temporary, number of lymph nodes containing cancer- divide, similar to those that limit proliferation period of time. We believe that a combined ous cells, which indicates whether the primary in cancer stem cells (for example, see ref. 6). strategy that concomitantly targets both the disease had spread at the start of treatment. These changes could be epigenetic — modu- tumour cells and the surrounding microenvi- However, even among women with small, lating gene expression without affecting the ronment has a higher probability of destroy- node-negative tumours, the risk of metastasis underlying DNA sequence — or genetic5. ing the dormant cells or of inducing a lifelong was about 10% over the 15-year period. Extrinsic factors include crosstalk between state of dormancy, and hence provides a higher Pan et al. acknowledge that there are different cell types in the surrounding micro- probability of a cure. A better understanding of several caveats to their analysis, including a environment, such as endothelial cells that line the crosstalk between the dormant cells, their lack of available data on how many women vessels, immune cells and fibroblasts, which surrounding cell types and the immune sys- completed their adjuvant treatment, and make up the structural framework of tissues. tem is crucial for developing effective micro- suboptimal treatment of people who had one A second dimension is vasculature-related environment-directed therapies. In addition, particular type of ER-positive breast cancer, dormancy, in which the tumour-cell popula- attention should be paid to the possibility dubbed HER2-positive. Nonetheless, it is clear tion is kept small because poor vascularization that dormant breast tumour cells undergo that, even after adjuvant endocrine therapy, in the region leads to a lack of nutrients and evolutionarily conserved programs that lead women with ER-positive, early-stage breast oxygen. A third dimension is immune-medi- to a stem-cell-like, prolonged resting state. cancer remain at persistent risk of recurrence ated dormancy, in which the immune system Maintaining this stem-cell status permanently for at least 20 years after the original diagno- controls an expanding tumour-cell population might be another way to prevent dormant cells sis. These findings, together with data from by continuously searching for and eliminating from reawakening. ■ another analysis of breast-cancer relapse2, cancerous cells. might have implications for long-term follow- If this dormancy status becomes unbalanced Giuseppe Curigliano is in the Department up strategies, and possibly for treatments. owing to changes in any of these factors, dor- of Hematology and Oncology, European One way to decrease the risk of relapse mant cells awaken and metastatic disease Institute of Oncology, University of Milan, might be to extend the duration of adjuvant develops. Thus, strategies to prevent relapse 20141 Milan, Italy. Fatima Cardoso is at the endocrine therapy — a strategy that is already should aim either to stop dormant cells from Breast Unit, Champalimaud Clinical Center, being tested. We wonder, however, whether awakening or to destroy them when dormant. Champalimaud Foundation, 1400–038 this approach will be sufficient to reduce or To achieve this goal, it would be beneficial to Lisbon, Portugal. avoid the risk of late metastasis. One trial3 identify those patients who will have a late e-mails: [email protected]; published in 2016 indicates that increasing relapse and to tailor a therapeutic strategy to [email protected] the duration of adjuvant therapy from five them. ER-positive breast cancers have a low 7 1. Pan, H. et al. N. Engl. J. Med. 377, 1836–1846 (2017). to ten years significantly improves rates of level of intratumoral cell diversity , such as 2. Colleoni, M. et al. J. Clin. Oncol. 34, 927–935 (2016). disease-free survival five years after the treat- distinct forms of genetic, epigenetic and func- 3. Goss, P. E. et al. N. Engl. J. Med. 375, 209–219 ment ceases, and lowers the incidence of can- tional diversity. A better understanding of (2016). 4. Colleoni, M. et al. Lancet Oncol. 19, 127–138 (2017). cer arising in the previously unaffected breast this diversity might lead to the identification 5. Goss, P. E. & Chambers, A. F. Nature Rev. Cancer 10, — but does not increase overall survival rates. of factors that enable certain cells to become 871–877 (2010). A second4 trial compared continuous adju- resistant to endocrine therapy and survive in 6. Tosoni, D. et al. EMBO Mol. Med. 9, 655–671 (2017). 7. Ellis, M. J. & Perou, C. M. Cancer Discov. 3, 27–34 vant therapy between years five and ten with metastatic niches. (2013). an ‘on–off’ therapy that aimed to resensitize Perhaps the major effect of extended adju- cancer cells that might have become resistant vant endocrine therapy is to keep tumour This article was published online on 29 January 2018. to the therapy. It found no difference in rates of metastasis-free survival on completion of either treatment. ORGANIC CHEMISTRY Longer follow-ups are needed to better understand the effects of extended adjuvant endocrine therapy, because of the slowly pro- gressive nature of the disease. Nonetheless, it Reactive carbon species is clear that, although extending the duration of therapy can play a part in preventing late relapses, it might well need to be given for the tamed for synthesis rest of a woman’s life to be effective. This would raise issues of toxicity, compliance and cost. A highly reactive form of carbon, known as a carbyne, holds great promise for To best determine other possible ways to organic synthesis, but has been difficult to prepare. Reactions that produce reduce the risk of relapse, we must consider carbyne equivalents now unleash this synthetic potential. See Letter p.86 what might cause the dormant tumour cells from which metastasis arises to reawaken after many years. Dormant cells have escaped ROHAN E. J. BECKWITH to new types of C–C bond-formation reaction. destruction by the body’s immune system Conventional approaches to C–C bond and entered a microenvironment that sup- he basis of organic chemistry is the study formation typically involve well-studied, ports their survival5. Once in this niche, of carbon-containing compounds with reactive carbon species. Carbynes, however, many mechanisms might underlie dormancy the aim of manipulating carbon atoms have been largely unexplored for C–C bond — indeed, dormancy can be thought of as a Tto generate new molecules through the forma- formation because their high reactivity makes multidimensional status, which involves mul- tion of carbon–carbon (C–C) bonds. On page them challenging to prepare and handle. Once tiple factors (Fig. 1). 86, Wang et al.1 report a method for harnessing formed, carbynes react with each other, with One dimension is cellular dormancy, in a reactive form of carbon known as a carbyne solvent molecules and with other substrates which intrinsic or extrinsic factors drive cells (Fig. 1a), which has been underused in syn- in an uncontrolled manner, producing myriad into a resting state. Intrinsic factors might thetic chemistry. The findings open the door products. This has limited their applications,

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NEWS & VIEWS RESEARCH

and even efforts to study these species. a Carbynes have previously been formed as C complexes with metals, which can then be Carbyne decomposed to release the free carbyne (see b refs 2 and 3, for example). By conducting such Mask decompositions in water at room temperature, researchers have prepared simple compounds Light EtO C Mask 2 Mask that contain C–C triple bonds from the reac- EtO C 4 EtO C 2 tions of free carbynes with each other . The 2 Precursor formation of undesired side products in these Mask Carbyne equivalent Mask reactions was minimized because the rate of reaction of the free carbynes with water c N OTf was several times slower than the rate of the 2 H 5 I O carbyne–carbyne reaction . However, product Me EtO C Me yields were low, and the method has limited 2 O CO Et Me 2 Me CO Et applications for synthesis. Catalyst, base, blue light, H 2 Wang et al. have devised a clever means of Precursor room temperature 32% yield accessing equivalents of carbynes, an approach

that has broad synthetic utility. The authors Me prepared stable precursor compounds that d Me OTf contain two ‘masking’ groups (Fig. 1b). These N2 N2 precursors can be activated by a catalyst in I O Me a light-mediated process so that one of the EtO2C O CO Et EtO2C masks is released, generating a carbyne equiv- 2 Catalyst, base, white light, Me room temperature Diazoacetate alent. Further activation allows the carbyne 73% yield equivalent to react with substrate molecules, losing the second mask and forming three new Figure 1 | Carbyne equivalents for synthetic chemistry. a, Carbynes are reactive carbon-containing bonds in a single synthetic step. species with potential uses in organic synthetic chemistry. Dots indicate electrons; black sphere represents The authors demonstrated the power of this any organic chemical group. b, Wang et al.1 report a strategy that allows equivalents of carbynes to be single-step approach by transforming isobutyl- prepared from precursor compounds that contain two ‘masking’ groups. One mask is removed in a light- benzene (a simple hydrocarbon that contains mediated process, generating the carbyne equivalent; square brackets indicate that the carbyne equivalent a benzene ring) into a more-complex system, is formed transiently. If the equivalent is generated in the presence of substrate molecules (coloured spheres), it reacts to form three new bonds in a single synthetic step, losing the second mask in the installing a new ring in a process that forms process. Et, ethyl group. c, In this colour-coded example, the authors’ precursor reacts with three different two new C–C bonds and one carbon–hydro- groups in a single molecule of isobutylbenzene, when irradiated with blue light at room temperature

gen (C–H) bond (Fig. 1c). The reaction occurs in the presence of a catalyst and a base. OTf, triflate (SO3CF3); Me, methyl. d, When white light is used, with high selectivity at particular carbon atoms diazoacetate products form in which one of the masks (a diazo group, red) is retained, as in this example. on isobutylbenzene, and under conditions that chemists would describe as very mild: at range of aromatic substrates. In each case, the for diazoacetate incorporation into drug ambient temperature and pressure, and using diazoacetate is positioned highly selectively molecules are often low to moderate (10–58%) reagents that tolerate the presence of a wide at a particular site — even for substrates that compared with the yields observed for the range of groups in the substrate molecule. contain bulky groups, which often erode site less-complex substrates (mostly 50–99%). Such conditions avoid unwanted degradation selectivity in other types of reaction. Moreover, Moreover, substrates that bear strongly elec- of the starting materials or the product, thus the reactions tolerate the presence of a variety tron-withdrawing groups on the aromatic maximizing the potential product yield. of chemical groups in the substrates, and give ring also seem to reduce yields and site selec- Wang and colleagues also showed that reasonable yields of products. tivity relative to other substrates. But these are the unmasking process could be conducted The diazoacetate group is especially useful minor issues compared with the benefits of this in a stepwise manner by modifying the for chemical synthesis because it can be con- approach for drug discovery and development. reaction conditions, allowing the isolation verted into many other groups using metal- Wang and colleagues’ work also has of compounds in which groups known as catalysed reactions (as Wang et al. demonstrate more-fundamental implications for organic diazoacetates are attached to benzene rings; one for diazoacetates made using their approach). chemistry. It offers a new means of generating of the masks is retained as part of the diazo­ The availability of a method that allows diazo compounds (the family of compounds to acetate group (Fig. 1d). Although methods for diazoacetate groups to be incorporated site which diazoacetates belong) that allows access making diazoacetates attached to benzene rings selectively into structurally complex mol- to types of diazo molecule that were not pre- have been reported previously, they require a ecules will be particularly useful for research- viously accessible using other chemistries. In synthetic ‘handle’ — a reactive atom or group ers working in drug discovery, because it will addition, because the reactions generate three — to be present on a benzene ring in the start- enable variants of biologically active molecules new bonds, they provide a way to convert sim- ing material6. The authors’ method installs to be made rapidly from the molecules them- ple reagents into structurally complex mole- diazoacetates directly at a C–H bond on a ben- selves, rather than in multi-step synthetic cules in a single step. The authors’ reactions zene ring, and so does not require a synthetic routes from simple starting materials. Indeed, are therefore an invaluable addition to the handle. It might, therefore, allow diazoacetates Wang et al. demonstrate effective, site-selective synthetic chemist’s toolbox. to be attached to complex aromatic systems diazoacetate incorporation into 12 complex Finally, Wang et al. have reported the first (compounds that contain a benzene ring, or drug molecules. evidence that carbynes can be harnessed effec- a related ring system) into which synthetic There are some limitations to the new tively for practical organic synthesis. The find- handles cannot be incorporated. reactions — for example, drug compounds ings therefore open the door to the exploration The authors show that the diazoacetate- that contain basic amine groups tend not to be of new reactivities of carbon — either through installing reaction works effectively for a amenable to this approach. The yields obtained modification of the currently reported masked

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RESEARCH NEWS & VIEWS carbyne equivalents, or through the develop- e-mail: [email protected] 12248–12251 (2013). ment of alternative ones. ■ 4. Bino, A., Ardon, M. & Shirman, E. Science 308, 1. Wang, Z., Herraiz, A. G., del Hoyo, A. M. & Suero, M. G. 234–235 (2005). Nature 554, 86–91 (2018). 5. Bogoslavsky, B. et al. Angew. Chem. Int. Edn 51, Rohan E. J. Beckwith is at the Novartis 2. Fischer, E. O., Ruhs, A. & Plabst, D. Z. Naturforsch. B 90–94 (2012). Institutes for BioMedical Research, Inc., 32B, 802–804 (1977). 6. Ye, F. et al. J. Am. Chem. Soc. 137, 4435–4444 Cambridge, Massachusetts 02139, USA. 3. Levy, O., Musa, S. & Bino, A. Dalton Trans. 42, (2015).

MARINE VIROLOGY gene transfer between species and the spread of viral infection. Bacteriophage action is usually studied using models in which a virus infects A non-tailed twist in only one or a small group of closely related host strains or species, because this is the pattern observed for most of the bacteriophages cul- the viral tale tured so far. And yet such cultures represent just a small proportion8 of the hundreds of Microscopy studies indicate that the most common viruses in the sea lack a tail known bacterial phyla9. structure. However, most cultured marine viruses have tails. A family of these Kauffman and colleagues sought to expand elusive non-tailed marine viruses has now been identified. See Letter p.118 the breadth of marine viruses known. They analysed water samples collected off the coast of Massachusetts on three separate days, and JULIO CESAR IGNACIO-ESPINOZA are predominantly non-tailed3–5. Therefore, attempted to identify bacteriophages that could & JED A. FUHRMAN identifying the ‘missing’ non-tailed marine infect any of the 1,334 strains of Vibrionaceae viruses might improve our understanding of bacteria that they had isolated. The Vibrion- acteriophages, the viruses that infect how viruses regulate the microbial systems that aceae are an easily cultured bacterial group that bacteria, are thought to be the most control a large fraction of global carbon and contains the cholera-causing pathogen Vibrio abundant biological entities on Earth1. nitrogen cycling2,6. Onn page 118, Kauffman cholerae, as well as more-benign relatives, such BIt has been estimated that, if lined up end to et al.7 report the discovery of a non-tailed viral as bioluminescent bacteria that form symbiotic end, bacteriophages from the oceans alone family that they suggest might be an impor- relationships with fishes and squid. would cover a distance of 3 million parsecs, tant component of the missing viruses, and Of all the bacteria that the authors tested, past many distant galaxies2. Most bacterio- they explain why this group might have eluded 239 strains became infected with viruses, phages cultured in the laboratory or repre- detection until now. and Kauffman et al. isolated 241 previously sented in DNA-sequence databases have a ‘tail’ Viruses can be key drivers of the evolution, unknown viruses, of which 18 were non-tailed. structure, which might take the form of a tube community composition and mortality of They named this non-tailed family (Fig. 1) the with spider-leg-like protrusions (similar in microorganisms, although their major role Autolykiviridae, after Autolykos, an elusive shape to the base of the Apollo Moon lander). in the oceans was not recognized until the thief from Greek mythology who could not be However, electron-microscopy analysis of 1990s2,6. The number of species a virus can caught. DNA-sequence analysis revealed that ocean samples indicates that oceanic viruses infect is a crucial factor that can influence autolykiviruses have small genomes (approxi- mately 10 kilobases in length), which diverge enough from those of known viruses to form a T4 virus b Previously identi ed c Autolykivirus their own distinct lineage. They differ from marine non-tailed virus other bacteriophages in sequences encoding a specific structural fold in a capsid protein, which forms the outer viral shell. The puta- Capsid 111 nm Lipid 60 nm 49 nm tive capsid-encoding sequences identified by 10 kb 10 kb Kauffman and colleagues were most like those 169 kb that encode a fold known as a double jelly roll. This fold was previously associated with non- tailed viruses, in contrast to the HK97 fold found in tailed bacteriophages10.

Tail To investigate the ecological role of autolykiviruses, the authors performed a monumental host-range analysis, testing the ability of their 241 marine-isolated viruses to infect and kill 318 of their marine bacte- Figure 1 | Different viral forms. Viruses that contain a tail structure are the most common type of rial strains. They found that the 18 non-tailed bacterium-infecting virus (bacteriophage) cultured in the laboratory or represented in DNA databases. autolykiviruses were responsible for a dis- However, in samples taken from marine environments, non-tailed viruses are more common3–5. 7 proportionately high number of bacterial cell Kauffman et al. report a previously unknown family of non-tailed marine viruses. a, T4, an example of deaths. This was mainly because the autolyki- a tailed virus. Its 169-kilobase genome is enclosed in a capsid structure, made of protein (dark purple), 15 5 viruses had a substantially wider host range that is 111 nanometres long . The average capsid length for tailed marine viruses is 65 nm. The tail structures in certain other types of tailed virus have a different shape from that of T4. b, The cortovirus than the tailed group, and could infect multiple PM2, one of the few non-tailed marine bacteriophages identified so far. PM2 has lipid (yellow) associated Vibrionaceae genera, whereas the tailed viruses with its capsid. Non-tailed marine viruses have an average capsid size5 of 54 nm. c, An autolykivirus, a studied could not. The authors therefore pro- member of a family of non-tailed marine viruses identified by Kauffman et al.7. The properties of these pose that the impact of autolykiviruses on the bacteriophages are consistent with the presence of lipid. marine environment might be fundamentally

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