This document summarizes recent research that more accurately measured the distance to the Large Magellanic Cloud (LMC) galaxy. A team called the Araucaria Project measured the distances to eight eclipsing binary stars in the LMC to determine a distance of 49.3 ± 0.5 kiloparsecs, which is accurate to 2.2%. This more precise measurement of the distance to the LMC will help astronomers better determine distances to more distant galaxies and improve our understanding of properties like dark energy. The new measurement is consistent with but more accurate than previous estimates, addressing issues with prior discrepancies in LMC distance measurements.

1. NEWS & VIEWS RESEARCH
double-stranded breaks followed by repair. analyse and address possible off-target effects and of Chemistry, University of California,
The gene-targeting achieved up to 38% success and improve the efficiency and specificity Berkeley, Berkeley, California 94720, USA,
and was accompanied by only a low level of of the system, while expanding its use to and in the Physical Biosciences Division,
Cas9 toxicity. The RNA-guided Cas9 was also other organisms. In this regard, it will be Lawrence Berkeley National Laboratory,
efficient at triggering targeted gene replace- important to compare RNA-programmed Berkeley.
ment at normal genomic sites in human cells. Cas9 with existing genome-editing tools18, e-mails: emmanuelle.charpentier
In another paper published in the same month, including meganucleases, ZFNs (zinc-finger @helmholtz-hzi.de;
Jinek et al.19 show that RNA-programmed Cas9 nucleases) and TALENs (transcription acti- doudna@berkeley.edu
functions in human cells to trigger site-specific vator-like effector nucleases). In addition
genome modifications, and that the ability of to genome editing, this approach offers the 1. Ishino, Y., Shinagawa, H., Makino, K., Amemura, M.
& Nakata, A. J. Bacteriol. 169, 5429–5433 (1987).
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limiting factor in this activity. silencing using an inactive Cas9 (ref. 20) or 3. Mali, P. et al. Science 339, 823–826 (2013).
On the basis of earlier observations that engineering Cas9 to have new functions, 4. Cho, S. W., Kim, S., Kim, J. M. & Kim, J. S. Nature
single-stranded DNA breaks can favour such as transcriptional activation. The dis- Biotechnol. 31, 230–232 (2013).
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homologous recombination and reduce off- covery and application of bacterial systems, (2013).
target mutagenesis, Mali et al.3 and Cong such as restriction enzymes and thermostable 6. Jiang, W., Bikard, D., Cox, D., Zhang, F. & Marraffini, L. A.
et al.2 also tested versions of Cas9 that have polymerases, have revolutionized molecular Nature Biotechnol. 31, 233–239 (2013).
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been shown7 to act as a nickase enzyme — one biology in the past. With RNA-guided Cas9 8. Jansen, R., Embden, J. D., Gaastra, W. & Schouls, L. M.
that breaks only one strand of a DNA mol- enzymes, bacteria now offer a versatile tool Mol. Microbiol. 43, 1565–1575 (2002).
ecule. The mutated enzymes had lower rates for rewriting genomic sequence information 9. Haft, D. H., Selengut, J., Mongodin, E. F. & Nelson, K. E.
of NHEJ but were as efficient as the wild-type that has the potential to reshape the genome- PLoS Comput. Biol. 1, e60 (2005).
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endonuclease at gene replacement triggered engineering landscape in biotechnology and Soria, E. J. Mol. Evol. 60, 174–182 (2005).
by homologous recombination. Both groups medicine. ■ 11. Pourcel, C., Salvignol, G. & Vergnaud, G.
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the system in ‘multiplexed’ targeting; the Emmanuelle Charpentier is at the Wolf, Y. I. & Koonin, E. V. Biol. Direct 1, 7 (2006).
expression of sgRNA-programmed Cas9 that Helmholtz Centre for Infection Research, 13. Barrangou, R. et al. Science 315, 1709–1712
can bind to two different genomic sequences Department of Regulation in Infection (2007).
led to sequence disruption at more than one Biology, 38124 Braunschweig, Germany, 14. Brouns, S. J. et al. Science 321, 960–964 (2008).
15. Deltcheva, E. et al. Nature 471, 602–607 (2011).
independent target site. In addition, Cong in the Laboratory for Molecular Infection 16. Garneau, J. E. et al. Nature 468, 67–71 (2010).
and colleagues show that gene-disruption effi- Medicine Sweden, Umeå University, 17. Sapranauskas, R. et al. Nucleic Acids Res. 39,
ciency could be improved upon independent Sweden, and at the Hanover Medical School, 9275–9282 (2011).
18. Carroll, D. Mol. Ther. 20, 1658–1660 (2012).
expression of the two RNA components of the Hanover, Germany. Jennifer A. Doudna 19. Jinek, M. et al. eLIFE http://dx.doi.org/10.7554/
original dual-tracrRNA–crRNA combination. is at the Howard Hughes Medical Institute, eLife.00471 (2013).
This finding implies that improved design of Departments of Molecular and Cell Biology 20. Qi, L. S. et al. Cell 152, 1173–1183 (2013).
sgRNAs may allow them to better mimic the
dual RNA structure7.
In addition to these results in cell lines, ASTR O PH YS I CS
RNA-guided Cas9 can be used to engineer
genomic changes in intact organisms. Jiang
and colleagues6 show that the system can be
used in bacteria to modify multiple sites by
An accurate distance
to the nearest galaxy
programming Cas9 with several different
guide RNAs in a single cell. This technology
could be exploited to engineer microorgan-
isms that are otherwise genetically intractable
to harbour pathways for producing biofuels By having a highly accurate value for the distance to the Large Magellanic Cloud
and molecules of therapeutic value. Working galaxy, astronomers can get a better measure of cosmic ‘dark energy’. Using
with zebrafish, Hwang and colleagues5 show binary stars, they have now achieved a value accurate to 2.2%. See Letter p .76
that injection of one-cell-stage embryos with
Cas9-encoding mRNA and appropriate guide
RNAs produced high frequencies (24–59%) BRADLEY E. SCHAEFER by means of a ‘distance ladder’: knowledge of
of targeted insertions and deletions at eight of the distances to nearby bodies is used to deter-
D
ten sites in all embryos tested. These findings istances to celestial bodies are crucial mine the distances of bodies farther out, and
hint that RNA-guided Cas9 might be useful in astronomy. They allow astrono- so on to yet more remote objects. On page 76
for engineering other multicellular organ- mers to understand the structure of of this issue, Pietrzyński et al.1 claim to pro-
isms, including mammals and plants. One of the Universe; for example, to see the organiza- vide a much-needed, highly accurate measure
the most exciting potential uses of such tech- tion of the Solar System and to recognize that of the distance to the Large Magellanic Cloud
nology would be to provide a straightforward galaxies lie beyond the Milky Way. The derived galaxy — the bottleneck in the ascent of the
means of generating animal models of human physical sizes of bodies scale with the distances distance ladder.
disease. adopted for them, whereas their energetics Historically, the lowest ‘rung’ of the distance
Genome engineering by RNA-pro- scale with the square of the distances. A cur- ladder, the size of Earth, was used to calibrate
grammable Cas9 promises to have broad rent hot enterprise is to use distance meas- the timings of the transit of Venus across the
applications in synthetic biology, direct urements to the farthest supernovae to map Sun, and so to climb to the second rung, the
and multiplexed perturbation of gene net- out the expansion history of the Universe Earth–Sun distance. The method of paral-
works, and targeted ex vivo and in vivo gene and to uncover the nature of the Universe’s lax — watching stars wobble back and forth
therapy2–7. The next challenges will be to mysterious dark energy. Distances are deduced as Earth orbits the Sun — was used to climb
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2. RESEARCH NEWS & VIEWS
A comparison of the new LMC distance with
CELESTIAL IMAGE CO./SPL
previously published values reveals three dis-
turbing issues. First, the Araucaria Project had
previously reported one of its eclipsing bina-
ries to have a distance of 50.1±1.4 kilo­parsecs10,
but it now quotes 49.3±0.5 kilo­parsecs for that
binary, with no indication of how its analysis
has changed. Second, and much more dis-
turbingly, the four eclipsing binaries reported
by the Villanova group5–8 have an average
distance of 47.1±1.4 kilo­ arsecs, which is
p
substantially different. The main difference
between the groups’ techniques is the use of
cool stars by the Araucaria Project, together
with an empirical surface-brightness-versus-
colour relation to determine the stars’ surface
temperature, as opposed to the use of hot
stars by the Villanova group and theoretical
models to infer the temperature. Third, the
new distance is remarkably close to the value
obtained by the Key Project, with a differ-
ence of only one-tenth of the error bar quoted
by Pietrzyński et al., so we should recall the
history of the bandwagon effect.
What can we expect in the future? Studies
of roughly a dozen more eclipsing binaries are
in the pipeline, with results expected soon.
Also, extensions of the technique will be made
to the eclipsing binaries in the galaxy M33, in
the constellation Triangulum. But the entire
scene will change when the Gaia spacecraft
is launched later this year, with its awesome
Figure 1 | The Large Magellanic Cloud. Pietrzyński et al.1 have determined an accurate distance to the capability for measuring accurate distances
Large Magellanic Cloud galaxy, the ‘anchor’ point from which distances to other galaxies can be measured. by means of the parallax, even out to the
LMC. Gaia will provide definitive calibration
to the third rung, the distance to nearby stars. published distances that slavishly followed this of various ‘standard candles’ used to climb
For cosmology and extra­galactic astronomy, value4. The 2011 Nobel laureate Adam Riess rungs above the LMC on the distance ladder,
almost all ways of climbing the distance and the SH0ES project have since adopted thereby eliminating the bottleneck at the LMC.
ladder pass through the rung of the Large a method pioneered by a group centred at Indeed, Gaia will obtain parallax data for many
Magellanic Cloud (LMC; Fig. 1), which is the Villanova University in Pennsylvania 5–8 stars in the LMC with the resultant average
evocatively named nearest galaxy to the Milky (involving four eclipsing binary stars) to obtain accurate to 1%, and will map out its struc-
Way. So if the LMC distance is off by 10%, an LMC distance of 49.8 kiloparsecs, with an ture. So the time spent by the LMC’s eclipsing
then the distances to all galaxies (as quanti- accuracy to 3% (ref. 9). binaries at the forefront of astrophysics will be
fied with the Hubble constant, the expan- Now Pietrzyński et al., as part of the interna- limited to only the next few years. ■
sion rate of the Universe) will be in error by tional Araucaria Project, derive a value that is
the same 10%. When combined with meas- accurate to 2.2%. They achieved this by meas- Bradley E. Schaefer is in the Department
ures of far-off supernovae, a highly accurate uring the distances to eight eclipsing binaries of Physics and Astronomy, Louisiana State
distance to the LMC will also substantially in the LMC. (Eclipsing binaries are two-star University, Baton Rouge, Louisiana 70803,
improve measurements of the properties of systems whose component stars regularly pass USA.
dark energy, and thereby potentially reveal directly in front of each other as viewed from e-mail: schaefer@lsu.edu
its nature. Earth.) They measured accurate sizes for both
1. Pietrzyński, G. et al. Nature 495, 76–79 (2013).
The distance to the LMC has long been a stars in each binary (from the durations of
2. Benedict, G. F. et al. Astron. J. 123, 473–484
contentious question. Published values over the eclipses and the measured velocities) and (2002).
the decades have been scattered, with val- their surface temperatures (from spectra of the 3. Freedman, W. L. et al. Astrophys. J. 553, 47–72
ues from the decade before 2001 alone hav- stars), thereby deriving the total intrinsic lumi- (2001).
ing a scatter of 36%, despite the fact that the nosity of each binary system. By comparing the 4. Schaefer, B. E. Astron. J. 135, 112–119
reported error bars are much smaller than this total luminosity and the observed brightness, (2008).
5. Guinan, E. F. et al. Astrophys. J. 509, L21–L24
scatter2. So it is clear that the many methods and using the inverse square law of light, they (1998).
used to determine the LMC distance had large then determined the distances to the binaries. 6. Fitzpatrick, E. L. et al. Astrophys. J. 564, 260–273
and unidentified systematic errors. In 2001, the This method inspires confidence because it (2002).
influential Hubble Space Telescope Key Project uses only undergraduate astronomy and phys- 7. Ribas, I., Fitzpatrick, E. L., Maloney, F. P., Guinan, E. F.
presented a middle value of the previous scatter ics (but very carefully done), and completely & Udalski, A. Astrophys. J. 574, 771–782 (2002).
8. Fitzpatrick, E. L., Ribas, I., Guinan, E. F., Maloney, F. P.
with a reasonable error bar (50.1 ± 2.3 kilo­ jumps over all the lower rungs of the distance
& Claret, A. Astrophys. J. 587, 685–700 (2003).
parsecs, or 163,400 ± 7,500 light years)3. But its ladder. The authors’ new distance to the LMC, 9. Riess, A. G. et al. Astrophys. J. 730, 119 (2011).
publication created a bandwagon effect, and for which is based on the average of the distances 10. Pietrzyński, G. et al. Astrophys. J. 697, 862–866
the next six years the astronomy community to the eight binaries, is 49.97±1.13 kiloparsecs. (2009).
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