INSIGHTS | PERSPECTIVES

in the functional separation of metabolism. CONSERVATION Importantly, the demonstration of divergent NAD+ metabolism in the nucleus and cytosol during adipocyte differentiation shows not The hidden of only that the two pools are distinct but that their separation represents a point of regula- tion in control of a physiological process. amphibian pathogens Analogous regulation likely applies to other metabolites such as acetyl–coenzyme Discovery of additional amphibian chytrid pathogens A (CoA) and S-adenosylmethionine (SAM), increases conservation concerns which are needed in the nucleus for histone acetylation and histone and DNA methyla- tion, respectively. Both acetyl-CoA and SAM By Karen Lips with the period of high commercial trade are thought to be present in the cell at levels in amphibians. The authors describe phylo- that can limit acetyltransferase and methyl- ince the discovery of the salamander genetic patterns of Bd as clustering into five transferase activity (9); yet, definitive mea- chytrid pathogen [Batrachochytrium main lineages—four of which were previously surements of these metabolites specifically salamandrivorans (Bsal)] (1), the identified (6) and one entirely new, geneti- within the nucleus are lacking. Nevertheless, world has been preoccupied with de- cally distinct, hyperdiverse lineage from the enzymes that produce acetyl-CoA and SAM termining where it does and does not Korean peninsula. The high genetic diversity are present and distinctly regulated within occur (2) so that policies can be imple- of this new Asian lineage differs from that of the nucleus (1, 2), and recent metabolic evi- Smented to prevent introduction into unaf- the other four lineages, all of which exhibit a Downloaded from dence also supports the notion of functional fected areas (3). Pathogenic chytrids cause pattern of genetic diversity typical of popu- separation between nuclear and cytosolic , a disease of the skin that lation fluctuations and/or natural selection pools of acetyl-CoA (10, 11). can cause mortality and die- In addition to prompting further inves- offs, including population tigation into the nuclear and cytosolic com- declines and species extinc-

partmentalization of metabolism, the Ryu et tions. In the United States— http://science.sciencemag.org/ al. study raises a number of intriguing ques- the world’s biodiversity hot tions about NAD+ metabolism in adipocytes spot for salamanders and and other cell types. NAD+ rises with calorie currently free of Bsal—a restriction and exercise and is proposed as a multinational scientific task mediator of their beneficial effects through force has been created to regulation of sirtuin activity (12). SIRT1 in test the susceptibility of na- particular could be affected by variations in tive species and to prepare nuclear NAD+ levels, raising questions about an emergency response the potential role of NAD+ compartmental- should Bsal be detected (4).

ization in regulating the myriad processes Meanwhile, attention to on May 31, 2018 controlled by SIRT1 (13). Furthermore, how Bsal’s better-known cousin might compartmentalized NAD+ metabolism B. dendrobatidis (Bd), an- integrate with other stimuli that affect NAD+ other chytrid pathogen that levels, such as aging, caloric restriction, and has decimated amphibian circadian oscillations (13)? How does nuclear populations around the NAD+ affect other cellular differentiation pro- world, has faded, in part cesses or responses to stimuli that are regu- because of perceptions that lated by PARPs or sirtuins, and how might once Bd is present, conser- dysregulation of compartmentalized NAD+ vation actions and policy production contribute to disease states or options are limited. On page present therapeutic opportunities? Notably, 621 of this issue, O’Hanlon The Brazilian pumpkin toadlet (Brachycephalus pitanga) is host to BdBrazil. NMNAT-1 is deleted in some cancers (14). The et al. (5) remind us that Bd findings of Ryu et al. will surely prompt nu- remains a serious threat to global amphibian and consistent with increases in spatial dis- merous important avenues of investigation. j biodiversity and clarify where and when Bd tribution or in the number of host species. came from and how it spread. This suggests that East Asia is the most likely REFERENCES O’Hanlon et al. use whole-genome sequenc- source of origin for amphibian chytrid patho- 1. S. Sivanand et al., Trends Biochem. Sci. 43, 61 (2018). 2. A. Kinnaird et al., Nat. Rev. Cancer 16, 694 (2016). ing of 234 Bd cultures taken from around the gens. O’Hanlon et al. also identify two new 3. K. W. Ryu et al., Science 360, eaan5780 (2018). globe to identify East Asia as the site of origin kinds of hybrid lineages, raising the possibil- 4. R. Gupte et al., Genes Dev. 31, 101 (2017). 5. X. Luo et al., Mol. Cell. 65, 260 (2017). of Bd, including the Global Panzootic Lineage ity that introductions of new lineages might 6. X. A. Cambronne et al., Science 352, 1474 (2016). (BdGPL), the invasive, hypervirulent form of produce more hybrid chytrids. Finally, the 7. M.-F. Langelier et al., J. Biol. Chem. 285, 18877 (2010). chytrid that has been implicated in losses of authors show that all Bd variants are present 8. A. S. H. Costa et al., Int. Rev. Cell Mol. Biol. 332, 213 (2017). 9. M. A. Reid et al., Nat. Cell Biol. 19, 1298 (2017). amphibians from six regions (5, 6). The au- in the commercial trade of amphibians (in- 10. S. Zhao et al., Cell Rep. 17, 1037 (2016). thors date the emergence of BdGPL to the cluding food, pets, and scientific specimens), 11. V. Bulusu et al., Cell Rep. 18, 647 (2017). 12. S. Imai et al., Trends Cell Biol. 24, 464 (2014). second half of the 20th century, consistent demonstrating contemporary intercontinen- 13. C. Cantó et al., Cell Metab. 22, 31 (2015). tal transmission and the failure of interna- 14. F. L. Muller et al., Nature 488, 337 (2012). Department of Biology, University of Maryland, College Park, tional biosecurity measures to control the

10.1126/science.aat6663 MD 20742, USA. Email: [email protected] spread of this pathogen. TORRES LOPEZ ALBERTO PHOTO:

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DA_0511Perspectives.indd 604 5/9/18 11:28 AM The implications of these new findings science programs might serve as an early NUCLEAR PHYSICS are wide ranging. For example, although warning system in some regions. BdGPL is globally distributed, other lin- Successful mitigation of the impacts of eages are geographically restricted. This chytridiomycosis is also lacking. No effec- Resolving the identifies areas that might be susceptible tive treatments exist for wild populations, to new invasions by these endemic lineages and policies restricting imports are only as and may explain variation in species re- strong as enforcement efforts (7). One of neutron sponses to infection (7, 8). Despite decades the most important advances in the global of research, quantitative studies of the im- response to Bsal was the development of pacts of chytridiomycosis on amphibian an emergency response plan (11, 12), in- lifetime puzzle populations are lacking from most areas, cluding the establishment of a Bsal task A measurement of trapped especially Asia (8). Demographic analyses force (4); such a coordinated effort is lack- are critical in providing robust estimates ing for Bd and could speed discovery and neutrons dramatically of demographic parameters such as species identify effective interventions. improves control of or population-specific survival and mortal- Both Bd and Bsal are notifiable diseases ity rates and population growth rates. In under the World Organisation for Animal systematic uncertainties addition, mark-recapture studies that fol- Health (OIE) standards, but, despite global low the fate of infected individuals are support, this agreement has lacked strong, needed to identify mechanisms underlying consistent enforcement. Strengthening ap- By Pieter Mumm the causes of population decline, persis- plication of the OIE standards should be a tence, or recovery and to identify effective first step. In the United States, new laws ree electrons and protons are stable, Downloaded from conservation measures. are needed to improve the ability of the but outside atomic nuclei, free neu- To control emerging infectious diseases U.S. Fish and Wildlife Service to monitor trons decay into a proton, electron, (EIDs), we also need a better understand- and control invasive species and diseases and antineutrino through the weak ing of the relative contributions of global (13). New policies developed in collabora- interaction, with a lifetime of ~880 s change (for example, changes in climate, tion with trade organizations, lobbyists, (see the figure). The most precise land use, and trade) on the emergence and national and international organiza- Fmeasurements have stated uncertainties http://science.sciencemag.org/ and spread of pathogens. Knowing that tions to implement quarantine measures, below 1 s (0.1%), but different techniques, all chytrid lineages are circulating in trade testing procedures, and clean-trade pro- although internally consistent, disagree routes, but not all are globally distributed grams could minimize the risk of pathogen by 4 standard deviations given the quoted (5), highlights the need for coinfection ex- introductions. The European Union has uncertainties. Resolving this “neutron life- periments to predict responses to future recently approved such a law (14). time puzzle” has spawned much experi- invasions. Knowledge of how the trade eco- The work of O’Hanlon et al. serves as mental effort as well as exotic theoretical system might amplify disease by promot- a case study for studying and addressing mechanisms, thus far without a clear ex- ing hybridization events among lineages or EIDs. With accelerating global change in by facilitating the spread of lineages into a more connected world, we can expect to

naïve populations could be useful to miti- see more EIDs, so international collabora- on May 31, 2018 gate and manage disease within the live- tions such as this one will be increasingly “Researchers have primarily animal trade. necessary to address global pathogens of used two techniques to Many areas of the world lack chytrid wildlife, agriculture, and humans. j cultures, disease surveillance programs, or measure the neutron amphibian population studies necessary REFERENCES 1. A. Martel et al., Science 346, 630 (2014). lifetime, typically referred to study or conserve amphibian biodiver- 2. T. A. Yap et al., Science 349, 481 (2015). sity. Developing collaborative partnerships 3. U.S. Department of the Interior, Fish and Wildlife Service, to as ‘beam’ and ‘bottle’ between investigators from these regions “50 CFR Part 16, Injurious wildlife species: Listing sala- manders due to risk of salamander chytrid fungus,” Fed. measurements.” and established research groups could in- Reg. 81, 1534 (2016). crease the global capacity to understand 4. M. J. Gray et al., PLOS Pathog. 11, e1005251 (2015). the emergence of Bd and responses of am- 5. S. J. O’Hanlon et al., Science 360, 621 (2018). planation. On page 627 of this issue, Pattie phibian populations. Even more important 6. R. A. Farrer et al., Proc. Natl. Acad. Sci. U.S.A. 108, 18732 et al. (1) present the most precise measure- (2011). is the need to expand veterinary capacity 7. T. W. J. Garner et al., Phil. Trans. R. Soc. B 371, 20160207 ment of the neutron lifetime to date. A new for wildlife diseases. Many national veteri- (2016). method of measuring trapped neutrons in nary authorities lack sufficient resources, 8. K. R. Lips, Phil. Trans. R. Soc. B 371, 20150465 (2016). situ allows a more detailed exploration of 9. B. A. Han et al., Proc. Natl. Acad. Sci. U.S.A. 112, 7039 staff, or bandwidth to respond effectively to (2015). one of the more pernicious systematic ef- the rapidly increasing numbers of wildlife 10. F. T. Burbrink et al., Sci. Adv. 3, e1701387 (2017). fects in neutron traps, neutron phase-space pathogens that threaten global biodiversity. 11. E. H. C. Grant et al., U.S. Geological Survey Open-File evolution (the changing orbits of neutrons Report 2015–1233 (2015); http://dx.doi.org/10.3133/ Proactive measures to address EIDs will ofr20151233. in the trap), than do previous methods. be possible when we can predict future out- 12. E. H. C. Grant et al., Front. Ecol. Environ. 15, 214 (2017). The precision achieved, combined with a breaks, species susceptibility, and disease 13. U.S. Government Accountability Office (GAO),“Live Animal very different set of systematic uncertain- Imports: Agencies Need Better Collaboration to Reduce spread, perhaps through analyses to model the Risk of Animal-Related Diseases” (Report GAO-11-9, ties, gives hope that experiments such as disease outbreaks from genomics, Google GAO, 2010). this one can help resolve the current situa- search histories, or social media data (9, 10). 14. European Commission (2018); http://eur-lex.europa.eu/ tion with the neutron lifetime. Advanced detection technologies would im- eli/dec_impl/2018/320/oj .

prove the ability to address new introduc- National Institute of Standards and Technology, 100 Bureau Drive tions. Alternatively, coordination of citizen 10.1126/science.aat6411 MS-8461, Gaithersburg, MD 20899, USA. Email: [email protected]

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