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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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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 />
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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 />
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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 />
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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