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Top-Down Versus Bottom-Up<br />

Euan Nisb<strong>et</strong>, <strong>et</strong> <strong>al</strong>.<br />

<strong>Science</strong> <strong>328</strong>, <strong>1241</strong> (<strong>2010</strong>);<br />

<strong>DOI</strong>: <strong>10.1126</strong>/<strong>science.1189936</strong><br />

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version of this article at:<br />

http://www.sciencemag.org/content/<strong>328</strong>/5983/<strong>1241</strong>.full.html<br />

This article cites 17 articles, 3 of which can be accessed free:<br />

http://www.sciencemag.org/content/<strong>328</strong>/5983/<strong>1241</strong>.full.html#ref-list-1<br />

This article appears in the following subject collections:<br />

Atmospheric <strong>Science</strong><br />

http://www.sciencemag.org/cgi/collection/atmos<br />

Downloaded from www.sciencemag.org on November 14, 2011<br />

<strong>Science</strong> (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the<br />

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<strong>2010</strong> by the American Association for the Advancement of <strong>Science</strong>; <strong>al</strong>l rights reserved. The title <strong>Science</strong> is a<br />

registered trademark of AAAS.


PERSPECTIVES<br />

CREDIT: NASA/DRYDEN/CARLA THOMAS<br />

tion experiments involving N nuclei have<br />

features in common with collective atomic<br />

radiation in the optic<strong>al</strong> domain ( 19, 20).<br />

Synchrotron x-ray photons weakly excite an<br />

ensemble of iron-57 nuclei with the proper<br />

timing in a slab. Röhlsberger <strong>et</strong> <strong>al</strong>. measured<br />

the tempor<strong>al</strong> evolution of the state decay<br />

and the collective Lamb shift by an<strong>al</strong>yzing<br />

the energy spectra of the radiation reflected<br />

from the sample. The collective Lamb shift<br />

<strong>al</strong>most doubled its v<strong>al</strong>ue when the particle<br />

number doubled.<br />

The experiments of yesterday and today<br />

use the atom or nucleus as a laboratory to<br />

study virtu<strong>al</strong> processes. As such, the tiny<br />

electromagn<strong>et</strong>ic level shifts have given us<br />

deep insights into nature. What about the<br />

future? Recent c<strong>al</strong>culations show that system<br />

dynamics can be strongly influenced<br />

by vacuum fluctuations ( 14, 21); that is, the<br />

collective Lamb shift can have a big effect<br />

on decay rates. For example, for a large<br />

atomic cloud, a symm<strong>et</strong>ric state |S〉 (see the<br />

second figure, panel B) is trapped. However,<br />

virtu<strong>al</strong> transitions couple it to decaying<br />

states, which results in a slow decay of<br />

the |S〉 state (see the second figure, panel<br />

D). On the other hand, virtu<strong>al</strong> photons only<br />

slightly change the evolution of the rapidly<br />

decaying states, such as the timed state |+〉<br />

(see the second figure, panel C). Nevertheless,<br />

they change the long time dynamics<br />

from the exponenti<strong>al</strong> decay into a powerlaw<br />

behavior.<br />

Many other interesting issues are associated<br />

with vacuum fluctuations. For example,<br />

the collective part of the many-atom<br />

Lamb shift is free of infinities ( 17). In addition,<br />

for very large atomic samples, memory<br />

effects become important and yield “a<br />

new kind of cavity QED” ( 12). The fascinating<br />

effects of virtu<strong>al</strong> photons on N-atom<br />

collective emission will be fertile ground<br />

for future research.<br />

ATMOSPHERIC SCIENCE<br />

Top-Down Versus Bottom-Up<br />

Euan Nisb<strong>et</strong> 1 and Ray Weiss 2<br />

Greenhouse gas emissions are currently<br />

quantified from statistic<strong>al</strong> data<br />

without testing the results against the<br />

actu<strong>al</strong> increases of these gases in the atmosphere.<br />

This is like di<strong>et</strong>ing without weighing<br />

oneself. Data are produced by greenhouse<br />

gas emitters of <strong>al</strong>l sizes, from factory or farm<br />

to nation, and are quoted to high precision—<br />

y<strong>et</strong> misreporting occurs, wh<strong>et</strong>her by simple<br />

error, ignorance, or intention. But now scientists<br />

on both sides of the Atlantic are arguing<br />

that regulation of greenhouse gas emissions<br />

can have integrity only if verified by direct<br />

atmospheric measurements ( 1, 2).<br />

Measurement m<strong>et</strong>hods have improved<br />

remarkably in the past few years, especi<strong>al</strong>ly<br />

with the advent of new optic<strong>al</strong> m<strong>et</strong>hods that<br />

provide continuous high-precision carbon<br />

dioxide (CO 2<br />

), m<strong>et</strong>hane (CH 4<br />

), and nitrous<br />

oxide (N 2<br />

O) data relatively inexpensively, and<br />

with prospects of added stable isotopic data.<br />

Modeling m<strong>et</strong>hodologies are under development<br />

that promise evolution from coarse<br />

glob<strong>al</strong>-sc<strong>al</strong>e understanding to resolution of<br />

region<strong>al</strong>- or country-sc<strong>al</strong>e emissions ( 3).<br />

1<br />

Department of Earth <strong>Science</strong>s, Roy<strong>al</strong> Holloway, University<br />

of London, Egham TW20 0EX, UK. 2 Scripps Institution of<br />

Oceanography, University of C<strong>al</strong>ifornia San Diego, La Jolla,<br />

CA 92093–0244, USA. E-mail: e.nisb<strong>et</strong>@es.rhul.ac.uk;<br />

rfweiss@ucsd.edu<br />

Currently, carbon-equiv<strong>al</strong>ent emissions<br />

are assessed by “bottom-up” m<strong>et</strong>hods,<br />

which aggregate disparate loc<strong>al</strong> statistics<br />

such as fuel consumption or numbers<br />

of cows. Glob<strong>al</strong>-sc<strong>al</strong>e emissions of some<br />

industri<strong>al</strong> greenhouse gases, as measured<br />

by their accumulation in the atmosphere,<br />

can disagree with reported bottom-up emissions<br />

by factors of two or more ( 4– 7). Atmospheric<br />

data <strong>al</strong>so suggest that actu<strong>al</strong> emissions<br />

of industri<strong>al</strong> greenhouse gases tend to<br />

be greater than reported.<br />

To carry out “top-down” assessment, that<br />

is, using atmospheric understanding to<br />

quantify emissions, an approach that<br />

integrates sever<strong>al</strong> m<strong>et</strong>hods is needed.<br />

First, the atmosphere must be measured<br />

at high spati<strong>al</strong> and tempor<strong>al</strong> resolution<br />

via n<strong>et</strong>works of ground-based<br />

stations and aircraft (see the figures).<br />

Second, remote sensing is needed,<br />

both from satellites to give glob<strong>al</strong> coverage<br />

and from the ground to c<strong>al</strong>ibrate<br />

the satellite data. Third, modeling synthesizes<br />

the results and assesses budg<strong>et</strong>s.<br />

As the data collection n<strong>et</strong>work<br />

and data interpr<strong>et</strong>ation through modeling<br />

improve, we can begin to envision<br />

their use to test and v<strong>al</strong>idate bottom-up<br />

inventories.<br />

References and Notes<br />

1. R. Röhlsberger <strong>et</strong> <strong>al</strong>., <strong>Science</strong> <strong>328</strong>, 1248 (<strong>2010</strong>); published<br />

online 13 May <strong>2010</strong> (<strong>10.1126</strong>/science.1187770).<br />

2. W. E. Lamb, R. C. R<strong>et</strong>herford, Phys. Rev. 72, 241 (1947).<br />

3. In his lectures, Lamb modestly c<strong>al</strong>led it the “electromagn<strong>et</strong>ic<br />

level shift.”<br />

4. P. A. M. Dirac, Proc. R. Soc. London Ser. A, 114, 243<br />

(1927).<br />

5. J. R. Oppenheimer, Phys. Rev. 35, 461 (1930).<br />

6. H. A. Kramers, Nuovo Cim. 15, 108 (1938).<br />

7. H. A. B<strong>et</strong>he, Phys. Rev. 72, 339 (1947).<br />

8. S. Triebwasser <strong>et</strong> <strong>al</strong>., Phys. Rev. 89, 98 (1953).<br />

9. A beautiful precision measurement of the 1S Lamb shift<br />

of atomic hydrogen and deuterium was pioneered in the<br />

study in ( 10).<br />

10. T. W. Hänsch <strong>et</strong> <strong>al</strong>., Phys. Rev. L<strong>et</strong>t. 34, 307 (1975).<br />

11. R. Dicke, Phys. Rev. 93, 99 (1954).<br />

12. M. O. Scully, A. A. Svidzinsky, <strong>Science</strong> 325, 1510 (2009).<br />

13. M. O. Scully, Laser Phys. 17, 635 (2007).<br />

14. A. A. Svidzinsky <strong>et</strong> <strong>al</strong>., Phys. Rev. A 81, 053821 (<strong>2010</strong>).<br />

15. S. Prasad, R. J. Glauber, Phys. Rev. A 31, 1583 (1985).<br />

16. R. Friedberg <strong>et</strong> <strong>al</strong>., Phys. Rep. C 7, 101 (1973).<br />

17. M. O. Scully, Phys. Rev. L<strong>et</strong>t. 102, 143601 (2009).<br />

18. W. R. Garr<strong>et</strong>t <strong>et</strong> <strong>al</strong>., Phys. Rev. L<strong>et</strong>t. 64, 1717 (1990).<br />

19. U. van Bürck, Hyperfi ne Interact. 123–124, 483 (1999).<br />

20. B. W. Adams, J. Mod. Opt. 56, 1974 (2009).<br />

21. R. Friedberg, Ann. Phys. 325, 345 (<strong>2010</strong>).<br />

<strong>10.1126</strong>/science.1190737<br />

Can nation<strong>al</strong> emissions inventories be verified<br />

through direct atmospheric measurements?<br />

Most emissions and many sinks are in<br />

the atmospheric boundary layer, the air<br />

next to the ground. Atmospheric contents<br />

become well mixed worldwide within a<br />

few years. However, loc<strong>al</strong> composition can<br />

vary greatly. For example, the CO 2<br />

atmospheric<br />

mixing ratio, currently about 388<br />

parts per million in the glob<strong>al</strong> background,<br />

can loc<strong>al</strong>ly be significantly reduced by the<br />

springtime growth spurt in a deciduous forest<br />

or rise dramatic<strong>al</strong>ly in urban winter rush<br />

hours. Long-term loc<strong>al</strong> measurements carry<br />

much information about sources and sinks.<br />

Measuring the atmosphere via aircraft. NASA’s Glob<strong>al</strong><br />

Hawk robotic aircraft—with a range of 20,000 km, an <strong>al</strong>titude<br />

capability above 18 km, and 30 hours of endurance—<br />

is being developed in collaboration with NOAA to measure<br />

and sample atmospheric greenhouse gases and other climate-relevant<br />

param<strong>et</strong>ers.<br />

Downloaded from www.sciencemag.org on November 14, 2011<br />

www.sciencemag.org SCIENCE VOL <strong>328</strong> 4 JUNE <strong>2010</strong> <strong>1241</strong><br />

Published by AAAS


PERSPECTIVES<br />

A ground-based station. The Sphinx high-<strong>al</strong>titude (3571 m) research station at the Jungfraujoch in the Bernese<br />

Alps, Switzerland, as seen from the M<strong>et</strong>Air atmospheric research aircraft. High-frequency measurements<br />

of greenhouse gases at this station are combined with similar measurements at other stations in Europe and<br />

around the globe in top-down modeling of region<strong>al</strong> greenhouse gas emissions.<br />

To obtain these data, air collected from towers<br />

feeds instruments that continuously<br />

record region<strong>al</strong> greenhouse gas variations.<br />

On remote coasts and islands, the marine<br />

background is monitored to map the glob<strong>al</strong><br />

state of the atmosphere, continuing the work<br />

begun by Charles David Keeling more than<br />

50 years ago ( 8).<br />

Multigas in situ records can be used to<br />

track season<strong>al</strong> and diurn<strong>al</strong> emission patterns<br />

and to test emissions declarations for<br />

intern<strong>al</strong> consistency ( 9). Single stations too<br />

are v<strong>al</strong>uable ( 10). Fluxes can be quantified<br />

loc<strong>al</strong>ly by comparison with otherwiseknown<br />

emissions, such as the radon isotope<br />

222<br />

Rn. If the CO 2<br />

/CH 4<br />

ratios in the loc<strong>al</strong><br />

air do not match inventory estimates for a<br />

major urban area, the inventory should be<br />

reexamined. Isotopes are powerful identifiers<br />

of sources, especi<strong>al</strong>ly if measurements<br />

are coupled with models of atmospheric<br />

transport and mixing. Fossil and nonfossil<br />

sources of CO 2<br />

can be differentiated by<br />

measuring 14 C in atmospheric CO 2<br />

( 11). The<br />

ratios of 13 C to 12 C in CH 4<br />

can differentiate<br />

b<strong>et</strong>ween w<strong>et</strong>land sources and clathrate and<br />

gas field sources.<br />

Aircraft studies are important, for example,<br />

in showing that CO 2<br />

uptake by tropic<strong>al</strong><br />

ecosystems is glob<strong>al</strong>ly important ( 12). Satellites<br />

add the wider dimension and will be<br />

especi<strong>al</strong>ly v<strong>al</strong>uable in tropic<strong>al</strong> regions where<br />

long-term in situ data are scarce. Currently,<br />

satellites such as the aging European Scanning<br />

Imaging Absorption Spectrom<strong>et</strong>er for<br />

Atmospheric Chartography (SCIAMACHY)<br />

instrument and Japan’s Greenhouse Gases<br />

Observing Satellite (GOSAT) are mapping<br />

carbon gases by means of reflected sunlight,<br />

and the United States is planning to<br />

replace its lost Orbiting Carbon Observatory<br />

(OCO) satellite. Quantitative verification<br />

of emissions inventories is still beyond<br />

the present generation of satellites, but partnership<br />

b<strong>et</strong>ween space-based observation<br />

and accurate ground-based in situ measurement<br />

promises much b<strong>et</strong>ter understanding<br />

of glob<strong>al</strong> carbon budg<strong>et</strong>s.<br />

Measurements of greenhouse gases in<br />

the air and knowledge of the winds and<br />

atmospheric transport are used in atmospheric<br />

transport inversions to test and<br />

assess emissions. Modeling studies based<br />

on records from many stations can quantify<br />

emissions over large regions, from nationsc<strong>al</strong>e<br />

to continents to glob<strong>al</strong> ( 5, 9, 13, 14).<br />

In western Europe, with the existing n<strong>et</strong>work<br />

of measurement stations, it may be<br />

possible to recover CO 2<br />

fluxes reliably on<br />

a sc<strong>al</strong>e of 1000 km and over a time period<br />

of 10 days ( 15, 16). This is close to what is<br />

needed for v<strong>al</strong>idating bottom-up emissions<br />

(which are quoted on an annu<strong>al</strong> basis). In<br />

the United States, NOAA’s CarbonTracker<br />

( 17) is a community tool that aims to produce<br />

quantitative estimates of atmospheric<br />

carbon uptake and release for North America<br />

and the rest of the world that are consistent<br />

with observed patterns of CO 2<br />

in the<br />

atmosphere.<br />

New modeling m<strong>et</strong>hods are <strong>al</strong>so being<br />

developed that will, for example, <strong>al</strong>low easy<br />

nesting of high-resolution region<strong>al</strong> models<br />

into glob<strong>al</strong>-sc<strong>al</strong>e models of atmospheric<br />

transport ( 18). For CO 2<br />

, much needs to be<br />

done to quantify biologic<strong>al</strong> fluxes ( 19),<br />

but this type of modeling is <strong>al</strong>ready being<br />

applied to CH 4<br />

and some industri<strong>al</strong> greenhouse<br />

gases. In Europe, large-sc<strong>al</strong>e inversion<br />

modeling of CH 4<br />

has been used to ch<strong>al</strong>lenge<br />

some nation<strong>al</strong> emissions inventories ( 20).<br />

The pressures of emissions control legislation<br />

and the v<strong>al</strong>ue of emissions reductions<br />

in carbon-equiv<strong>al</strong>ent trading mark<strong>et</strong>s create<br />

strong incentives for intention<strong>al</strong> underreporting<br />

and for inequity among nations.<br />

Legislators need to acknowledge that large<br />

uncertainties in emissions exist, and promote<br />

advances in both bottom-up and topdown<br />

assessments so that they agree within<br />

specified uncertainties. Perhaps 5% would<br />

be a re<strong>al</strong>istic initi<strong>al</strong> targ<strong>et</strong>.<br />

Cooperative glob<strong>al</strong> monitoring is not<br />

new. The Comprehensive Test Ban Treaty<br />

Organization has undertaken a program<br />

to locate and quantify atmospheric emissions<br />

of radioisotopes based on a n<strong>et</strong>work<br />

of ground-based measurement stations and<br />

inverse modeling of atmospheric transport.<br />

Why not begin by adding greenhouse<br />

gas measurements to these stations? The<br />

successful use of this approach to monitor<br />

greenhouse gas emissions at nation<strong>al</strong><br />

and subnation<strong>al</strong> sc<strong>al</strong>es will surely demand<br />

a much b<strong>et</strong>ter glob<strong>al</strong> n<strong>et</strong>work of high-frequency<br />

in situ measurements than we currently<br />

have, but the investment would not<br />

be great compared to the economic cost of<br />

failed regulation.<br />

Indeed, compared to the sc<strong>al</strong>e of the<br />

climate problem, in situ measurements,<br />

and even satellites, are relatively sm<strong>al</strong>l<br />

investments. But verification of emissions<br />

demands a sustained multiyear effort that<br />

can be anathema to current approaches to<br />

research support, especi<strong>al</strong>ly as the work has<br />

a strong discovery component. It <strong>al</strong>so needs<br />

to be supported, at least in part, through<br />

peer-reviewed research channels. Rigorous<br />

qu<strong>al</strong>ity control is essenti<strong>al</strong> if data from different<br />

m<strong>et</strong>hods and programs are to be adequately<br />

integrated. The results will be accurate<br />

within modeled error, based on direct<br />

CREDIT: BORIS SCHNEIDER/METAIR<br />

Downloaded from www.sciencemag.org on November 14, 2011<br />

1242<br />

4 JUNE <strong>2010</strong> VOL <strong>328</strong> SCIENCE www.sciencemag.org<br />

Published by AAAS


PERSPECTIVES<br />

measurement, and independent of reporting<br />

bias. Such verification may be critic<strong>al</strong> to a<br />

future comprehensive convention on climate<br />

change.<br />

References<br />

1. Committee on M<strong>et</strong>hods for Estimating Greenhouse Gas<br />

Emissions, Verifying Greenhouse Gas Emissions: M<strong>et</strong>hods<br />

to Support Internation<strong>al</strong> Climate Agreements (Nation<strong>al</strong><br />

Research Council, Washington, DC, <strong>2010</strong>).<br />

2. Roy<strong>al</strong> Astronomic<strong>al</strong> Soci<strong>et</strong>y Workshop Report, Verification<br />

of Greenhouse Gas Emissions by Atmospheric Measurement;<br />

www.ras.org.uk//index.php?option=com_<br />

content&task=view&id=936&Itemid=12.<br />

3. M. Marquis, P. Tans, <strong>Science</strong> 320, 460 (2008).<br />

4. I. Levin <strong>et</strong> <strong>al</strong>., Atmos. Chem. Phys. 10, 2655 (<strong>2010</strong>).<br />

5. A. Stohl <strong>et</strong> <strong>al</strong>., Atmos. Chem. Phys. 9, 1597 (2009).<br />

6. J. Mühle <strong>et</strong> <strong>al</strong>., Atmos. Chem. Phys. Discuss. 10, 6485<br />

(<strong>2010</strong>).<br />

7. R. F. Weiss, J. Mühle, P. K. S<strong>al</strong>ameh, C. M. Harth, Geophys.<br />

Res. L<strong>et</strong>t. 35, L20821 (2008).<br />

8. C. D. Keeling, Tellus 12, 200 (1960).<br />

9. I. Pison, P. Bousqu<strong>et</strong>, F. Chev<strong>al</strong>lier, S. Szopa, D. Hauglustaine,<br />

Atmos. Chem. Phys. 9, 5281 (2009).<br />

10. D. Lowry, C. W. Holmes, N. D. Rata, P. O’Brien, E. G. Nisb<strong>et</strong>,<br />

J. Geophys. Res. 106 (D7), 7427 (2001).<br />

11. I. Levin, C. Rödenbeck, Naturwissenschaften 95, 203<br />

(2008).<br />

12. B. B. Stephens <strong>et</strong> <strong>al</strong>., <strong>Science</strong> 316, 1732 (2007).<br />

13. P. P. Tans <strong>et</strong> <strong>al</strong>., <strong>Science</strong> 247, 1431 (1990).<br />

14. Y.-H. Chen, R. G. Prinn, J. Geophys. Res. 111 (D10),<br />

D10307 (2006).<br />

15. C. Carouge, P. Bousqu<strong>et</strong>, P. Peylin, P. Rayner, P. Ciais,<br />

Atmos. Chem. Phys. 10, 3107 (<strong>2010</strong>).<br />

16. C. Carouge <strong>et</strong> <strong>al</strong>, Atmos. Chem. Phys. 10, 3119 (<strong>2010</strong>).<br />

17. Nation<strong>al</strong> Oceanic and Atmospheric Administration,<br />

www.esrl.noaa.gov/gmd/ccgg/carbontracker/index.html.<br />

18. C. Rödenbeck, C. Gerbig, K. Trusilova, M. Heimann,<br />

Atmos. Chem. Phys. 9, 5331 (2009).<br />

19. M. V<strong>et</strong>ter <strong>et</strong> <strong>al</strong>., Biogeosciences 5, 561 (2008).<br />

20. P. Bergamaschi <strong>et</strong> <strong>al</strong>., Atmos. Chem. Phys. 5, 2431<br />

(2005).<br />

<strong>10.1126</strong>/<strong>science.1189936</strong><br />

CREDIT: Y. GREENMAN/SCIENCE<br />

VIROLOGY<br />

Helping the Resistance<br />

Phylogen<strong>et</strong>ic an<strong>al</strong>ysis reve<strong>al</strong>s mutations that<br />

led to the rise of drug resistance in season<strong>al</strong><br />

H1N1 influenza.<br />

Edward C. Holmes 1,2<br />

The evolution of antivir<strong>al</strong> drug resistance<br />

sounds like a simple Darwinian<br />

story. The high mutation rate that<br />

characterizes RNA viruses ensures that drugresistant<br />

mutations are generated continuously,<br />

and the glob<strong>al</strong> use of antivir<strong>al</strong>s provides<br />

the selection pressure for these mutations<br />

to sweep through vir<strong>al</strong> populations. In some<br />

cases, however, re<strong>al</strong>ity is more complex. The<br />

mutations that confer antivir<strong>al</strong> resistance may<br />

have a d<strong>et</strong>riment<strong>al</strong> effect on vir<strong>al</strong> fitness in the<br />

absence of the drug so that secondary fitnessrestoring<br />

mutations must occur to enable the<br />

large-sc<strong>al</strong>e spread of resistance. More puzzling,<br />

drug resistance can <strong>al</strong>so occur in the<br />

absence of the main agent of<br />

selection—the widespread use of<br />

antivir<strong>al</strong> drugs. Both of these evolutionary<br />

conundrums are appar-<br />

100<br />

ent in one of the most important<br />

cases of antivir<strong>al</strong> resistance in<br />

80<br />

recent years—the glob<strong>al</strong> spread<br />

of resistance to oseltamivir in season<strong>al</strong><br />

H1N1 influenza A virus. On<br />

60<br />

page 1272 of this issue, Bloom<br />

<strong>et</strong> <strong>al</strong>. ( 1) show that in a “permissive”<br />

gen<strong>et</strong>ic background, season<strong>al</strong><br />

H1N1 virus avoids the fit-<br />

40<br />

ness costs norm<strong>al</strong>ly associated<br />

with oseltamivir resistance.<br />

20<br />

The evolutionary ancestry<br />

of season<strong>al</strong> H1N1 influenza A<br />

virus lies with the devastating 0<br />

pandemic of 1918. Although the<br />

1<br />

Center for Infectious Disease Dynamics,<br />

Department of Biology, The Pennsylvania<br />

State University, University Park, PA<br />

16802, USA. 2 Fogarty Internation<strong>al</strong> Center,<br />

Nation<strong>al</strong> Institutes of He<strong>al</strong>th, B<strong>et</strong>hesda, MD<br />

20892, USA. E-mail: ech15@psu.edu<br />

Frequency (%)<br />

1918 virus eventu<strong>al</strong>ly died out in the 1950s,<br />

the H1N1 lineage reappeared in 1977 and<br />

has since circulated with H3N2 influenza<br />

A virus, and more recently with the newly<br />

emerged swine-origin pandemic H1N1/09<br />

virus. Although season<strong>al</strong> H1N1 is associated<br />

with lower mort<strong>al</strong>ity than either the H3N2 or<br />

pandemic H1N1/09 viruses, in some years it<br />

is the dominant strain infecting humans and<br />

a considerable public he<strong>al</strong>th concern. It was<br />

therefore worrying that in the winter of 2007–<br />

2008, the influenza season in the Northern<br />

Hemisphere, reports of oseltamivir resistance<br />

in season<strong>al</strong> H1N1 began to appear in northern<br />

Europe and in patients who had not received<br />

2000 2002 2004 2006 2008<br />

Year<br />

oseltamivir ( 2, 3). By the following 2008–<br />

2009 influenza season, it was clear that season<strong>al</strong><br />

H1N1 virus was resistant to oseltamivir<br />

on a glob<strong>al</strong> sc<strong>al</strong>e ( 4– 6), effectively ruling out<br />

further use of this frontline antivir<strong>al</strong> drug.<br />

Vir<strong>al</strong> neuraminidase cleaves termin<strong>al</strong><br />

si<strong>al</strong>ic acid residues from glycoproteins on<br />

the surface of an infected host cell, thereby<br />

promoting the release of progeny viruses.<br />

Oseltamivir binds to the neuraminidase and<br />

blocks this function. Resistance to oseltamivir<br />

is often associated with a histidine (H) to<br />

tyrosine (Y) amino acid change at residue<br />

274 (H274Y) of the influenza neuraminidase.<br />

Bloom <strong>et</strong> <strong>al</strong>. reaffirmed that in the absence<br />

of oseltamivir the H274Y<br />

mutation has a d<strong>et</strong>riment<strong>al</strong><br />

effect on vir<strong>al</strong> fitness. For the<br />

mutation to become “fixed”<br />

on a glob<strong>al</strong> sc<strong>al</strong>e—that is,<br />

occur at 100% frequency in<br />

the vir<strong>al</strong> population—it is<br />

therefore essenti<strong>al</strong> that the<br />

Influenza virus<br />

neuraminidase<br />

mutations<br />

H274Y<br />

V234M<br />

R222Q<br />

The rise of oseltamivir resistance. The graph depicts the changing glob<strong>al</strong> frequency of<br />

neuraminidase mutations associated with oseltamivir resistance in season<strong>al</strong> H1N1 influenza<br />

A virus from 2000 to 2009. The H274Y mutation is the main resistant d<strong>et</strong>erminant.<br />

Mutations V234M and R222Q arose earlier and were permissive to the spread of H274Y.<br />

Numbers were c<strong>al</strong>culated from <strong>al</strong>l H1N1 neuraminidase sequences available at GenBank.<br />

negative fitness effect is offs<strong>et</strong><br />

by secondary mutations<br />

located elsewhere in the<br />

vir<strong>al</strong> genome. Bloom <strong>et</strong> <strong>al</strong>.<br />

used a phylogen<strong>et</strong>ic an<strong>al</strong>ysis<br />

of H1N1 gene sequences<br />

to identify those amino acid<br />

changes that occurred in the<br />

vir<strong>al</strong> lineage that eventu<strong>al</strong>ly<br />

developed oseltamivir resistance,<br />

and hence before the<br />

H274Y mutation appeared.<br />

This an<strong>al</strong>ysis reve<strong>al</strong>ed two<br />

amino acid substitutions<br />

in the neuraminidase protein<br />

that seemed to preempt<br />

H274Y—replacement<br />

Downloaded from www.sciencemag.org on November 14, 2011<br />

www.sciencemag.org SCIENCE VOL <strong>328</strong> 4 JUNE <strong>2010</strong> 1243<br />

Published by AAAS

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