particles’ indistinguishability, which means
thatthereisnomeasurabledifferencebetween
the two outcomes in which the particles exit
alongdifferentpaths.Theoveralloutputphases
of these indistinguishable outcomes are opposite
to each other, and when added together
using quantumrulesforbosons(particleswith
integer spin, a quantum property common to
both photons and helium-4 atoms), these two
possible outcomes interfere and cancel. The
only outcomes remaining are those with two
particles in a single output. As a result, simul-
taneoussingle-particledetections(‘coincidence
counts’) at both outputs are forbidden.
Lopes et al. demonstrate two-particle
quantum interference with helium-4 atoms.
In their experiments, the atoms’ paths are
related to their speeds, which are manipulated
by selectively transferring momentum
to and from light in absorption and emission
processes5,6
. First, the researchers prepared a
‘twinpair’byremovingfromanatomreservoir
indistinguishable atoms with different speeds.
Second, they used light pulses to modify the
atoms’ momenta and cause the pair to meet;
the atom in the first path travels with velocity
v1 and the atom in the second path with v2.
A beam-splitting mechanism implemented
reflection and transmission by changing the
atoms’ speeds with 50% probability from v1 to
v2 and vice versa.
The atoms continued to travel until they hit
a time-resolved, multipixel atom-counting
detector, at which an atom withv1 wouldarrive
at a different time from one with v2. Lopes and
colleagues prepared many twin pairs in a short
interval and recorded the precise location and
timing of the atoms’ arrivals at the detector: a
coincident count would be the measurement
at a particular location of a particle at time t1
followed by a measurement at t2. Although
the researchers found that the arrivals from
the many pairs were distributed in two time
windows (corresponding to the two output
paths), they found a striking lack of instances
among these random outcomes when the
time difference was exactly t2 −t1, indicating
that the atoms from a twin pair must be exiting
the beam-splitter with the same velocity.
This‘anticorrelation’isthesignatureofaHOM
experiment.
As in quantum-optics demonstrations
of the HOM effect, the present result demonstrates
that pairs of identical, ‘quantumentangled’
particles have been produced. The
unique capabilities of this apparatus, including
the combination of condensed meta­stable
helium-4 atoms and the atom-counting detector,
offer a spatial and temporal resolution
unavailable to others. Protocols for transmitting
and processing quantum information,
analogous to those used in optical systems,
can now be implemented with new capabilities
in atomic systems: atoms, unlike photons,
may interact with one another, and because
they have mass, their mechanical properties,
such as momentum, can be varied and used as
experimental parameters.
Furthermore, because atoms can also be
fermions(particleswithhalf-integerspin,such
as electrons), they could exhibit a quantuminterference
effect that is the fermionic equivalent
of the HOM effect4
. Evidence for this
mechanismhasalreadybeenseeninelectronic
systems7
. The bosonic HOM effect demonstrated
here, and its fermionic counterpart,
may offer new possibilities for implementing
quantum-informationprotocolsandforexploring
the foundations of quantum physics.■
Lindsay J. LeBlanc is in the Department of
Physics, University of Alberta, Edmonton,
Alberta T6G 2E1, Canada.
e-mail: lindsay.leblanc@ualberta.ca
1.	 Hong, C. K., Ou, Z. Y. & Mandel, L. Phys. Rev. Lett. 59,
2044–2046 (1987).
2.	 Lopes, R. et al. Nature 520, 66–68 (2015).
3.	 Ou, Z. Y. & Mandel, L. Am. J. Phys. 57, 66 (1989).
4.	 Loudon, R. Phys. Rev. A 58, 4904–4909 (1998).
5.	 Campbell, G. K. et al. Phys. Rev. Lett. 96, 020406
(2006).
6.	 Bonneau, M. et al. Phys. Rev. A 87, 061603
(2013).
7.	 Neder, I. et al. Nature 448, 333–337 (2007).
CANCER
A piece of the p53 puzzle
An iron-dependent form of cell death called ferroptosis has been implicated as
a component of the tumour-suppressor activity of p53, providing fresh insight
into how this protein prevents cancer development. See Article p.57
KATHRYN T. BIEGING & LAURA D. ATTARDI
T
he gene that encodes the p53 tumoursuppressor
protein is the most com-
monlymutatedgeneinhumancancers1
.
Indeed, p53 is inactivated in more than half
of all cancers, reflecting the fact that it provides
a crucial brake to cancer development,
and that incapacitating p53 is often a requisite
step for the emergence of cancer. However,
despite years of research, our understanding
of how p53 performs its job remains far from
complete. In this issue, Jiang et al.2
(page 57)
uncover a previously unknown role for p53 in
regulating a type of cell death dubbed ferroptosis,
completing one more piece of the p53
puzzle.
Conventionally, p53 is thought of as a
sentinel for DNA damage. In this role as a
guardian of the genome, p53 responds to
DNA damage either by putting the brakes
on proliferation, allowing cells to pause and
repair damaged DNA before dividing, or by
driving a form of cell suicide called apoptosis,
both of which protect against the accumulation
of mutant cells that have the potential to
Stress signal
p53
Cell-cycle
arrest
Senescence Apoptosis
Tumour suppression
DNA repairMetabolic
regulation
Ferroptosis
SLC7A11
ROS
Figure 1 | The functions of p53 in tumour suppression.  Activation of p53 in response to stress signals
leads to diverse cellular responses. Conventionally, the tumour-suppressor activity of p53 has been
attributed to its ability to induce cell-cycle arrest, senescence and a form of cell death called apoptosis in
response to DNA damage or the expression of cancer-promoting genes. However, studies indicate that
other p53-mediated activities, such as metabolic regulation or DNA repair, might be needed for tumour
suppression, or might compensate when these classical functions are absent. Jiang et al.2
show that
p53 represses the target gene SLC7A11 to promote the accumulation of reactive oxygen species (ROS),
triggering a non-apoptotic form of cell death called ferroptosis that suppresses tumour growth.
2 A P R I L 2 0 1 5 | V O L 5 2 0 | N A T U R E | 3 7
NEWS & VIEWS RESEARCH
© 2015 Macmillan Publishers Limited. All rights reserved
fuel cancer development3,4
. The protein fulfils
this responsibility in large part by serving as a
transcription factor that, among its many target
genes, modulates the expression of genes
encoding proteins that inhibit cell division or
induce apoptosis4
.
Although this regulatory role as a guardian
of the genome seems to account for p53’s
tumour-suppressor function, several studies
have altered our thinking about how p53
represses cancer development. A set of papers
(including one from the authors of the current
study) provided pivotal evidence that
p53-mediated apoptosis and proliferative
arrest in response to DNA-damage signals are
dispensable for tumour suppression5–7
. These
studies illuminated the functions of p53 that
are not essential for tumour suppression, but
failed to definitively reveal which p53 functions
are required. Jiang and colleagues’ latest
study sheds light on this issue.
The authors use a mutated form of p53
called p533KR
, which carries alterations at several
key sites in its DNA-targeting region. As
such, p533KR
has an impaired ability to activate
many of p53’s target genes, including those
responsible for the protein’s anti-proliferative
and pro-apoptotic activity. The mutated
protein nonetheless suppresses spontaneous
tumour development in mice6
— but how?
The authors embark on an unbiased quest to
answer this question by searching for potential
mediators of p53 tumour-suppressor function.
They identify SLC7A11 as a gene whose
expressionisrepressedbybothp53andp533KR
.
SLC7A11 is a cell-surface, amino-acid
transporter protein that dampens the production
of reactive oxygen species (ROS), which
can wreak havoc in a cell by inducing dam-
age8
. In particular, by limiting ROS accumulation,
SLC7A11 inhibits ferroptosis, a form
of non-apoptotic cell death triggered by the
iron-dependent production of ROS9
(Fig. 1).
Jiang et al. show that both p53 and p533KR
can stimulate ferroptosis in vitro in response
to the ferro­ptosis-activating agent erastin,
and that this response can be inhibited by the
over­production of SLC7A11. This contrasts
starkly with the inability of p533KR
to regulate
classical p53 functions, and suggests that
the ability to induce ferroptosis could account
for the function of p533KR
in mice.
To test this hypothesis, the authors analyse
mouse embryos carrying p533KR
but lacking
the protein Mdm2, an essential inhibitor
of p53. These mutant embryos normally die
as a result of hyperactive p53 signalling, but
the authors show that inhibiting ferroptosis
imparts some protection against this lethality.
These experiments provide evidence that ferroptosis
contributes to p53 activity in vivo, in
this case promoting embryonic lethality.
Expanding this analysis to cancer development,
Jiang and colleagues next show that
overexpression of SLC7A11 overcomes
the tumour-suppressor effects of p533KR
in
tumours transplanted into mice. This suggests
that repression of SLC7A11 transcription is
necessary for p533KR
-mediated tumour sup-
pression,and,moreover,thatp533KR
suppresses
tumour growth at least in part through ferroptosis.
However, it remains unclear whether
p53-mediated activation of ferroptosis is a
front-line tumour-suppressive response or
whether it primarily provides a back-up mechanism
when other p53 functions are crippled,
as in the p533KR
mutant.
This study unveils a new pathway for
p53-dependent tumour suppression. However,
many questions remain. For instance,
it is still unknown whether ferroptosis is a
general mechanism that operates in all tumour
types or whether it has a more selective function,
suppressing cancers that originate from
specific tissues. It is also not yet clear which
p53-activating signals — such as expression
of cancer-promoting genes or deprivation of
nutrients — activate ferroptosis in vivo. The
roles of other p53 target genes in ferroptosis
must also be defined.
Inthebroaderlandscape,itwillbeimperative
to determine which other p53-dependent
processes contribute to tumour suppression
and what their context dependencies may
be10
. Although DNA-damage-induced apoptosis
and cell-cycle arrest have been deemed
to be dispensable for tumour suppression, this
does not preclude a role for these responses in
some settings. Finally, the finding that inducing
ferroptosis by using an erastin analogue
delays the growth of p53-expressing tumours
in a mouse transplant model11
suggests that
activating ferroptosis may be a promising
therapeutic strategy for treating tumours in
which p53 activity is retained, a possibility that
warrants further investigation. ■
Kathryn T. Bieging and Laura D. Attardi
are in the Department of Radiation Oncology,
Stanford University School of Medicine,
Stanford, California 94305-5152, USA.
L.D.A. is also in the Department of Genetics,
Stanford University School of Medicine,
e-mail: attardi@stanford.edu
1.	 Freed-Pastor, W. A. & Prives, C. Genes Dev. 26,
1268–1286 (2012).
2.	 Jiang, L. et al. Nature 520, 57–62 (2015).
3.	 Lane, D. P. Nature 358, 15–16 (1992).
4.	 Vousden, K. H. & Prives, C. Cell 137, 413–431
(2009).
5.	 Brady, C. A. et al. Cell 145, 571–583 (2011).
6.	 Li, T. et al. Cell 149, 1269–1283 (2012).
7.	 Valente, L. J. et al. Cell Rep. 3, 1339–1345 (2013).
8.	 Conrad, M. & Sato, H. Amino Acids 42, 231–246
(2012).
9.	 Dixon, S. J. et al. Cell 149, 1060–1072 (2012).
10.	Bieging, K. T., Mello, S. S. & Attardi, L. D. Nature Rev.
Cancer 14, 359–370 (2014).
11.	Yang, W. S. et al. Cell 156, 317–331 (2014).
This article was published online on 18 March 2015.
BIODIVERSITY
Land use matters
A meta-analysis at a local scale reveals that land-use change has caused species
richness to decline by approximately 8.1% on average globally, mainly as a result
of large increases in croplands and pastures. See Article p.45
BRIAN MCGILL
T
he main effects humans have on our
planet seem to manifest in factors of
two: we have doubled the rate at which
nitrogen enters the biosphere by using fertilizer;
we have diverted half of the fresh water
and half of all plant productivity for our own
purposes; and we have modified about half of
the planet’s land1,2
. It is widely speculated that
the last of these — modifying roughly 50% of
all land — is the biggest human-caused threat
to biodiversity, but this theory has never been
comprehensively assessed. On page 45 of this
issue, Newbold et al.3
describe an ambitious
attempt to evaluate the global impact of landuse
change on terrestrial biodiversity.
The authors assembled a data set of more
than 380 previous studies comparing the
biodiversity of sites with no human change
(original or primary vegetation) with similar
sites modified for human use. They combined
this data set with further data on the global
land-use changes made by humans over
the past 500 years4
, and also with several predictions
of how humans might modify land
use over the next 100 years. The processes
controlling biodiversity are highly scale-spe-
cific5
, and most previous studies have focused
either on extinctions at global scales or on the
number of species in certain regions (and the
latteris actually often increasing6
). By contrast,
Newbold et al. analysed their data at a local
scale, typically smaller than a football field,
which is more relevant to the way humans
interact with nature.
The headline finding is that land-use change
hascausedthenumberofspecies(speciesrichness)
contained in these small plots of land to
decline by 8.1% over 500 years when averaged
across the globe. The authors also find a 10.7%
decline in the number of individual organisms,
with an additional decline in richness
resulting from this loss of individuals rather
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